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Chng, Wee-Joo, Gaofeng Huang, Peter Leif Bergsagel, and Rafael Fonseca. "Identification of Cellular Pathways Mediating Progression of Monoclonal Gammopathy (MGUS) to Multiple Myeloma (MM) Using Gene Expression Profiling (GEP)." Blood 112, no. 11 (November 16, 2008): 1673. http://dx.doi.org/10.1182/blood.v112.11.1673.1673.
Повний текст джерелаАнотація:
Abstract Events mediating transformation from pre-malignant MGUS to MM is currently not well defined. Recurrent genetic abnormalities such as t(11;14), t(4;14), hyperdiploidy and chromosome 13 deletion are already present in MGUS at relatively similar frequency to MM. The unified deregulation of D-type cyclins is also already present in MGUS. Previous GEP studies have revealed little differences between MGUS and MM. A more recent study using a large patient cohort and new generation Affymetrix genechip identifies an MGUS signature but the functional and biological significance underlying this signature is unknown. In the current study, we analyze a cohort of 22 MGUS and 101 MM from the Mayo Clinic with GEP performed on Affymetrix U133A genechip using gene set enrichment analysis, a method that analyze differentially expressed gene between 2 phenotypes of interest in the context of published or curated genesets that represent specific biological, chemical, or molecular perturbation to cells. This method increases the sensitivity of identifying low but significant changes in gene expression. We made further modification to the original method that allows assessment in individual samples rather than the average across a phenotype further increasing the specificity of the output. In this analysis, 313 genesets were significant enriched for genes over-expressed in MM compared to MGUS, representing potential activated pathways that mediate transformation. When MM samples and genesets were clustered using the enrichment score for each genesets and samples, 4 cluster of genesets emerged, one including a number of MYC genesets, one including a number of cell cycle related genesets, one including genesets related to metabolic activity and another including a number of IFN related genesets. Further dissection of these correlated genesets to identify common enriched genes (leading edge genes) led to identification of a MYC core signature, tRNA core signature, Proteosome core signature and metabolic core signature which are highly correlated. From known literature and biology, it is likely that MYC activation leads to downstream activation of protein synthesis (tRNA signature), degradation (proteasome signature), and metabolic pathway (metabolic signature). This is verified by GEP results from in vitro modulation of MYC activation in cell lines. In addition, a cell cycle core signature and IFN core signature was identified. Activation of IFN and MYC core signatures accounts for almost 90% of MM patients. The remaining patients have a metabolic signature without MYC or IFN activation. The activation of the different core signatures is significantly correlated with certain TC classes when assessed by Chi-Square test. IFN activation is significantly correlated with D1 subtypes and negatively correlated with D2 subtypes. MYC activation is negatively correlated with t(11;14). Similar patterns were observed in a validation dataset of 351 MM patients from UAMS (GSE2677) with GEP performed on the U133plus2.0 chip. These results are validated at the protein level using IHC on TMA of the Mayo cohort. The activation of the IFN and MYC pathway may represent predominant mechanism in MGUS to MM progression.
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Seguier, Julie, Elisabeth Jouve, Mickaël Bobot, Elisabeth Whalen, Bertrand Dussol, Stéphanie Gentile, Stéphane Burtey, et al. "Paradoxical association between blood modular interferon signatures and quality of life in patients with systemic lupus erythematosus." Rheumatology 59, no. 8 (November 27, 2019): 1975–83. http://dx.doi.org/10.1093/rheumatology/kez541.
Повний текст джерелаАнотація:
Abstract Objectives Blood transcriptomic IFN signature is a hallmark of SLE. The impaired health-related quality of life (HRQOL) observed in SLE is poorly related to disease activity. The aim of this study was to test how IFN signatures were associated with HRQOL in SLE patients. Methods Among consecutive patients, blood transcriptomic profiles were analysed with a modular framework comprising 3 IFN modules: M1.2, M3.4 and M5.12. Disease activity was evaluated by the SLEDAI score, and HRQOL was assessed with the SF-36 questionnaire, which includes eight domains: physical function, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health (MH) and physical component summary and mental component summary scores. Results A total of 57 SLE patients were evaluated, among whom 27 (47%) were clinically quiescent, 30 (53%) were flaring, and 19 (33%) had active lupus nephritis. All SF-36 domains were altered in SLE patients compared with the general French population (P < 0.0001). In multivariate analysis, taking into account flares, age, ethnicity, smoking and renal severity, social functioning was independently associated with the IFN score (P = 0.027). Analyses restrained to quiescent patients (n = 27) yielded greater associations between social functioning and the three IFN modules, and between MH and M3.4. Considering all quiescent visits (n = 51), the IFN score was independently correlated with social functioning (P = 0.022) and MH (P = 0.038). Conclusion This unexpected paradoxical association between IFN signature and some specific HRQOL domains argues against a pivotal role of IFNs in the persistently altered HRQOL of SLE patients.
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Raupov, R., E. Suspitsin, R. Mulkidzhan, and M. Kostik. "POS1312 ANALYSIS OF INTERFERON TYPE I SIGNATURE IN JUVENILE DERMATOMYOSITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 993.3–994. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3292.
Повний текст джерелаАнотація:
Backgroundthe crucial role of hyperactivation IFN I signaling pathway has been proved in the pathogenesis of dermatomyositis. IFN I genes and chemokines activity vary according to subtype of inflammatory myopathies. IFN type 1 signature could be measured using different genes in the blood, skin and muscle tissue [1].Objectivesto evaluate IFN-score in children with dermatomyositis and compare with disease activityMethods15 patients (5 boys and 10 girls) were enrolled in the study. Clinical and laboratory parameters, disease activity (CMAS-childhood myositis assessment tool, aCAT- abbreviated cutaneous assessment tool) and treatment were assessed. Patients were compared accordingly to IFN-score elevation. IFN I-score was assessed by RT-PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1); median relative expression of ≥ 2 was considered as a cut-off. IFN I-score was evaluated in dynamics in 9 patients.Resultsmedian age of patients was 6.2 (3.6; 7.6) years. Skin and muscle involvement were in all patients, arthritis in 5 (33%) patients, calcinosis in 3 (20%), lipodystrophy in 2 (13%) and lung involvement in 5 patients (33%), and 9 patients (60%) had positive myositis-related antibodies. Ten patients (67%) had an active disease, while elevated IFN-signature was detected in 12 (80%) patients.Cumulative IFN I-score and its’ five components were higher in active patients, compare to inactive (13.6 vs 1.4, p=0.006).Patients with increased IFN I-score had lower CMAS score and higher aCAT score compare to patients with normal levels of IFN I-score. IFN-I score correlated with aCAT, arthritis and lung involvement.ConclusionIFN-I score may be considered as disease activity biomarker in juvenile dermatomyositis with predominantly skin activity process.References[1]Rigolet M, Hou C, Baba Amer Y, Aouizerate J, Periou B, Gherardi RK et al. Distinct interferon signatures stratify inflammatory and dysimmune myopathies. RMD Open. 2019 Feb 26;5(1):e000811. doi: 10.1136/rmdopen-2018-000811. PMID: 30886734; PMCID: PMC6397431.AcknowledgementsThis work was supported by the RSF grant № 20-45-01005Disclosure of InterestsNone declared
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van den Hoogen, Lucas L., Joël A. G. van Roon, Jorre S. Mertens, Judith Wienke, Ana Pinheiro Lopes, Wilco de Jager, Marzia Rossato, et al. "Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome." Annals of the Rheumatic Diseases 77, no. 12 (September 5, 2018): 1810–14. http://dx.doi.org/10.1136/annrheumdis-2018-213497.
Повний текст джерелаАнотація:
ObjectiveThe interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature.MethodsSerum levels of galectin-9, CXCL-10 (IP-10) and tumour necrosis factor receptor type II (TNF-RII) were measured in patients with SLE, SLE+APS and primary APS (PAPS) and healthy controls (n=148) after an initial screening of serum analytes in a smaller cohort (n=43). Analytes were correlated to measures of disease activity and the IFN signature. The performance of galectin-9, CXCL-10 and TNF-RII as biomarkers to detect the IFN signature was assessed by receiver operating characteristic curves.ResultsGalectin-9, CXCL-10 and TNF-RII were elevated in patients with SLE, SLE+APS and PAPS (p<0.05) and correlated with disease activity and tissue factor expression. Galectin-9 correlated stronger than CXCL-10 or TNF-RII with the IFN score (r=0.70, p<0.001) and was superior to CXCL-10 or TNF-RII in detecting the IFN signature (area under the curve (AUC) 0.86). Importantly, in patients with SLE(±APS), galectin-9 was also superior to anti-dsDNA antibody (AUC 0.70), or complement C3 (AUC 0.70) and C4 (AUC 0.78) levels in detecting the IFN signature.ConclusionGalectin-9 is a novel, easy to measure hence clinically applicable biomarker to detect the IFN signature in patients with systemic autoimmune diseases such as SLE and APS.
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Puig, Montse, Kevin Tosh, Lucja Grajkowska, and Daniela Verthelyi. "Differential IFN signature for TLR7 and 9 agonists (136.16)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 136.16. http://dx.doi.org/10.4049/jimmunol.184.supp.136.16.
Повний текст джерелаАнотація:
Abstract Innate immune response modulators that stimulate TLR7 and 9 activate similar signaling pathways but their therapeutic range is distinct. Moreover, 3 structurally different types of stimulatory sequences for TLR9 have been identified (CpG ODN type D/A, B/K and C) that act on the same receptor but activate distinct immunostimulatory pathways and elicit different clinical effects. This study characterizes and compares gene expression in human and macaque cells treated with different TLR7 & 9 agonists. In vitro results showed that overall TLR7 and 9 agonists elicit transcription of a similar repertoire of immune-related genes; however the magnitude and kinetics of the gene expression differed significantly, particularly for IFN-related genes as well as cell mobilization and adhesion genes. Interestingly, while transcription level and kinetics of type I IFNs gene expression in cells treated with CpG ODN D, B and C differed significantly, the relative distribution of IFNα subtypes was almost identical. In contrast, the same cells stimulated with the TLR7 agonist elicited a different pattern of IFNα subtypes and IFNα-inducible genes. In vivo, only rhesus macaque monkeys treated with CpG ODN type D showed a robust IFN type I response both locally and systemically. The data suggest a higher mobilization and activation of the pDC with CpG ODN type D treatment. Understanding the nature of these differences has implications for the therapeutic application of TLR agonists in humans.
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Mahdi, Haider, Peter Graham Rose, Fadi W. Abdul-Karim, Bradley J. Monk, and Ying Ni. "The role of proinflammatory immune (IFN-gamma) gene signature in predicting prognosis and response to chemotherapy in uterine carcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14209-e14209. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14209.
Повний текст джерелаАнотація:
e14209 Background: Immunotherapy is promising option given low toxicity and potential durable response. In mismatch repair proficient endometrial and ovarian cancers, the reported response rate is ranging from 10-15% in recurrent setting. We need to better identify subset of patients who benefits from immunotherapy. Multigene immune signatures represent a robust means of capturing a complex, T cell–inflamed phenotype necessary for the clinical activity of PD-1–/PD-L1–directed monoclonal antibodies. IFN-γ is a key cytokine produced by activated T cells, as well as natural killer (NK) and NK T cells, in the tumor microenvironment. An immune-related IFN-γ 18-gene profile was derived through a cross-validated penalized regression modeling strategy to predict response to anti-PD1 therapy across 9 different tumor types. We want to test if this gene panel can also predict cancer outcome and response to chemotherapy. Methods: We used whole transcriptome sequencing of RNA matched tumor-normal samples from 38 high stage (Stage III and IV) uterine serous cancer patients. All patients received chemotherapy with platinum and taxanes. IFN-18 gene expression score was calculated by averaging the normalized and log transformed individual gene read counts. The optimized score cut off was selected to best separating the progression free survival. Then the cut off score was tested in The Cancer Genomic Atlas (TCGA) uterine and ovarian cancer RNAseq datasets. Results: The IFN score of 2.46 was determined based on 18-gene expression derived from 38 high-stage uterine serous cancer samples. Average age was 67 years (range: 56-82 years). Uterine serous cancer is known to be MSI stable. Patients with score higher than 2.46 showed significantly longer progression free survival (PFS – 57.6 months vs 15months, p = 0.002) and longer overall survival (73.1 months vs 51.1 months), not statistically significant given our small sample size, p = 0.13) compared to the patients with score lower than 2.46. Then this IFN based gene signature was then applied to TCGA 541 uterine cancer samples with RNAseq data. Similarly, this signature predicted significant improvement in both progression-free survival (p = 0.001) and overall survival (p = 0.005). Interestingly, this score cannot separate outcome for TCGA ovarian cancer cohort. Conclusions: Immune-related IFN-γ gene signature predicted prognosis and response to chemotherapy. We plan to assess if this signature will predict endometrial cancer patients who benefits from anti-PD1 therapy.
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Wigston, Z., A. Burska, A. Alase, K. Mahmoud, and E. Vital. "OP0091 A TWO-SCORE INTERFERON SIGNATURE AND MUSCULOSKELETAL IMAGING EXPLAIN THE ASSOCIATION BETWEEN INTERFERON AND ARTHRITIS IN SLE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 60.2–60. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3564.
Повний текст джерелаАнотація:
Background:Interferon (IFN) signature is associated with disease activity and flare in SLE. We previously described two independent IFN gene expression scores; IFN Score A (the most commonly measured ISGs) and IFN Score B (less commonly measured ISGs which may also respond to IFN-II or other immune mediators)[1]. Many more clinical outcomes are associated with IFN Score B than with a “classic” interferon signature. These include progression of At-Risk individuals to SLE, response to rituximab, and differentiation of IFN signature in RA and SLE.In previous work, the relationship of IFN Signatures with arthritis was less clear than for other SLE features. This may be related to the local regulatory effects of IFN-beta in the synovium, contrasting with the pro-inflammatory effects of other interferons. Another reason may be the proven imprecision of clinical examination as a measure of MSK inflammation in SLE.USEFUL was a multicentre longitudinal study including serial ultrasound assessment of SLE patients with inflammatory MSK pain receiving treatment with glucocorticoids (GC).Objectives:To determine whether IFN scores A and B are associated with imaging-proven synovitis in SLE and measure the responsiveness of IFN scores to GC treatment.Methods:133 SLE patients were recruited into the USEFUL study if the referring physician deemed they had inflammatory pain warranting treatment. Participants received depomedrone 120mg IM then were assessed at 0, 2 and 6 weeks using clinical instruments and ultrasound (US). OMERACT US criteria were used to categorise patients as active (GS2 or PD1 in at least one joint or tendon), active in both joints and tendons, or non-active (no GS1 and PD0 or better in all joints).Expression of 26 interferon stimulated genes, normalised to PP1A was measured in whole blood collected in TEMPUS tubes using a custom Taqman array. IFN scores A and B were calculated as previously described[1]. Missing data was imputed using expectation-maximisation method. Parametric tests were applied with post hoc Tukey to compare scores between groups.Results:At baseline, there was no significant difference in IFN Score A between ultrasound groups (F = 1.045, p = 0.355). In contrast, IFN Score B differed significantly between ultrasound groups (F = 4.168, p = 0.018). The greatest difference was between active ultrasound for both joints and tendons (n=22) and non-active ultrasound (n=53) (difference = 0.75, 95% CI 0.13, 1.37, p=0.013).There was no significant change from baseline in IFN Score A at week 2 (mean difference 0.08, 95% -0.14, 0.31, p = 0.45) or week 6 (mean difference -0.03, 95% -0.25, 0.19, p = 0.79). Similarly, there was no significant change in IFN Score B at week 2 (mean difference -0.01, 95% -0.18, 0.17, p = 0.93) or week 6 (mean difference -0.07, 95% -0.21, 0.08, p = 0.36).Conclusion:Previous studies were unable to demonstrate an association between a typical interferon signature and arthritis in SLE. Our study includes a homogenous patient population and therapy, objective measure of synovitis, and a more detailed assessment of IFN Status. We found that imaging-proven synovitis is associated with increased expression of a specific subset of ISGs (IFN score B), but not a the more typical interferon signature genes (IFN Score A).This increases the body of evidence for the value of IFN score B in predicting clinical outcomes. GC treatment did not affect systemic IFN signature scores at follow up. Future analysis will explore the role of IFN Scores in predicting clinical responses to therapy in this study.References:[1]El-Sherbiny, Y.M., et al. Scientific Reports, 2018.8(1): p. 5793.Disclosure of Interests:Zoe Wigston: None declared, Agata Burska: None declared, Adewonuola Alase: None declared, Khaled Mahmoud: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK
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Blokland, Sofie L. M., Lucas L. van den Hoogen, Emmerik F. A. Leijten, Sarita A. Y. Hartgring, Ruth Fritsch, Aike A. Kruize, Joel A. G. van Roon, and Timothy R. D. J. Radstake. "Increased expression of Fas on group 2 and 3 innate lymphoid cells is associated with an interferon signature in systemic lupus erythematosus and Sjögren’s syndrome." Rheumatology 58, no. 10 (April 8, 2019): 1740–45. http://dx.doi.org/10.1093/rheumatology/kez116.
Повний текст джерелаАнотація:
Abstract Objective The role of innate lymphoid cells (ILCs) in the pathophysiology of rheumatic diseases is emerging. Evidence from animal studies implicate type I IFN, produced by plasmacytoid dendritic cells, to be involved in regulating the survival of group 2 and group 3 ILCs (ILC2s and ILC3s) via the upregulation of Fas (CD95) expression. For the first time, we explored the frequency and phenotype of circulating ILCs in SLE and primary Sjögren’s syndrome (pSS) in relationship to the IFN signature. Methods Frequencies and phenotypes of ILC subsets and plasmacytoid dendritic cells were assessed by flow cytometry in peripheral blood of patients with SLE (n = 20), pSS (n = 20) and healthy controls (n = 17). Patients were stratified by the presence or absence of an IFN signature as assessed by RT-qPCR on circulating mononuclear cells. Results ILC1 frequencies were increased in peripheral blood of patients with SLE as compared with healthy controls and correlate with disease activity in pSS patients. Overall, the frequencies of ILC2s or ILC3s did not differ between patients with SLE, pSS and healthy controls. However, patients with a high type I IFN signature expressed elevated levels of Fas on ILC2s and ILC3s, which coincided with decreased frequencies of these cells in blood. Conclusion The presence of a type I IFN signature is related to Fas expression and frequencies of circulating ILC2s and ILC3s in patients with SLE and pSS, potentially altering the homeostatic balance of ILCs.
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Pin, Alessia, Lorenzo Monasta, Andrea Taddio, Elisa Piscianz, Alberto Tommasini, and Alessandra Tesser. "An Easy and Reliable Strategy for Making Type I Interferon Signature Analysis Comparable among Research Centers." Diagnostics 9, no. 3 (September 4, 2019): 113. http://dx.doi.org/10.3390/diagnostics9030113.
Повний текст джерелаАнотація:
Interferon-stimulated genes (ISGs) are a set of genes whose transcription is induced by interferon (IFN). The measure of the expression of ISGs enables calculating an IFN score, which gives an indirect estimate of the exposition of cells to IFN-mediated inflammation. The measure of the IFN score is proposed for the screening of monogenic interferonopathies, like the Aicardi-Goutières syndrome, or to stratify subjects with systemic lupus erythematosus to receive IFN-targeted treatments. Apart from these scenarios, there is no agreement on the diagnostic value of the score in distinguishing IFN-related disorders from diseases dominated by other types of cytokines. Since the IFN score is currently measured in several research hospitals, merging experiences could help define the potential of scoring IFN inflammation in clinical practice. However, the IFN score calculated at different laboratories may be hardly comparable due to the distinct sets of IFN-stimulated genes assessed and to different controls used for data normalization. We developed a reliable approach to minimize the inter-laboratory variability, thereby providing shared strategies for the IFN signature analysis and allowing different centers to compare data and merge their experiences.
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Del Papa, Nicoletta, Antonina Minniti, Maurizio Lorini, Vincenzo Carbonelli, Wanda Maglione, Francesca Pignataro, Nicola Montano, Roberto Caporali, and Claudio Vitali. "The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives." Biomolecules 11, no. 2 (February 9, 2021): 251. http://dx.doi.org/10.3390/biom11020251.
Повний текст джерелаАнотація:
There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.
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Shi, Yuhao, Melissa Dolan, Michalis Mastri, Kevin Eng та John Ebos. "249 Targeting IFNβ-regulated secretory profiles to overcome acquired anti-PD-L1 resistance". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (листопад 2020): A270. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0249.
Повний текст джерелаАнотація:
BackgroundTherapeutic targeting of programmed cell death protein ligand 1 (PD-L1) has led to durable benefits for many cancer patients; however, the development of acquired resistance is common. Dysregulated type II interferon (IFN) signaling on tumor cells can contribute to resistance via altered expression of IFN stimulated genes (ISGs), which include cytokines and growth factors capable of immune-suppression and tumor promotion. However, the role of type I IFNs, including IFNα and IFNβ, in acquired resistance remain understudied. Here we examined the impact of chronic PD-L1 blockade to evaluate the role of IFN-related secretory changes in preclinical models of resistance.MethodsUsing a mouse breast EMT6 orthotopic tumor model, we selected PD-L1 drug resistant (PDR) cells from tumors initially responsive to PD-L1 blockade, but that later relapsed. Using transcriptomic and proteomic approaches, we evaluated secreted proteins associated with IFN signaling. To test for direct connections between PD-L1 and IFN signaling in secretory profile modulation, genetic and therapeutic disruption of PD-L1/IFNAR1 were conducted in vitro.ResultsWe identified a unique gene signature for secreted proteins following acquired resistance to PD-L1 blockade that associated with IFN signaling. This secretory signature was validated using publicly available datasets derived from preclinical tumors and clinical biopsies after anti-PD-L1 treatment failure. Interestingly, genetic and antibody inhibition of PD-L1 in vitro enhanced PDR secretory signatures following IFNβ stimulation suggesting PD-L1 tumor-intrinsic functions may regulate IFN responses following acquired resistance. To test whether secretory profiles impact tumor growth, inhibition of specific ISGs (IL-6) or ISG regulators (IFNAR1) were examined and found to inhibit PDR tumors in vivo, compared to parental controls.ConclusionsTogether, these findings identify a secretory profile associated with acquired resistance to PD-L1 blockade that may be modulated, at least in part, by IFNβ. Selective targeting of secreted ISGs may provide a benefit for patients after anti-PD-L1 treatment failure.
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Shobha, Vineeta, Anu Mohan, AV Malini, Puneet Chopra, Preethi Karunanithi, Siva Subramani Thulasingam, Sabariya Selvam, et al. "Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature." Lupus 30, no. 5 (January 26, 2021): 762–74. http://dx.doi.org/10.1177/0961203321990107.
Повний текст джерелаАнотація:
Objective Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. Methods We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. Results Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. Conclusions Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.
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Grenn, Robert C., Srilakshmi Yalavarthi, Alex A. Gandhi, Nayef M. Kazzaz, Carlos Núñez-Álvarez, Diego Hernández-Ramírez, Antonio R. Cabral, W. Joseph McCune, Paula L. Bockenstedt, and Jason S. Knight. "Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome." Annals of the Rheumatic Diseases 76, no. 2 (July 18, 2016): 450–57. http://dx.doi.org/10.1136/annrheumdis-2016-209442.
Повний текст джерелаАнотація:
ObjectivesPatients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS.MethodsWe studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes.ResultsEndothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody.ConclusionsWe describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.
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Lee, Elinor, Xiuli Xu, Peter Munson, Ronald Cooper, Nalini Raghavachari, Therese White, Gerald E. Marti, Wyndham H. Wilson, and Adrian Wiestner. "Rituximab Induces an Interferon Gene Expression Signature in Patients with CLL." Blood 108, no. 11 (November 16, 2006): 4988. http://dx.doi.org/10.1182/blood.v108.11.4988.4988.
Повний текст джерелаАнотація:
Abstract Rituximab, a monoclonal anti-CD20 antibody, is used to treat Chronic Lymphocytic Leukemia (CLL) in combination with fludarabine. Rituximab is thought to deplete B-cells through antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and possibly signaling for apoptosis. Whether or not signaling by rituximab contributes to its clinical efficacy and can sensitize the malignant cells to chemotherapy is controversial. To investigate if rituximab can induce a specific gene expression signature, we used genomic-scale gene expression profiling (Affymetrix HU133A 2.0 arrays) of B-cells from CLL patients receiving their first rituximab infusion. During the infusion, patients experienced a cytokine release syndrome (fever, chills, and hypotension) that led to interruption and symptomatic treatment in most; however, all patients were able to finish the treatment. Absolute lymphocyte counts decreased on average by 50% over this initial 24h period. We analyzed CD19+ selected CLL cells from eight patients obtained pre and 6 and 24 hours after the start of rituximab. A one-way ANOVA test was used to identify genes up- or down-regulated with a false discovery rate (FDR = number of expected chance findings / number of observations) of <10%. We identified 80 genes with at least 1.5× higher expression at 6h versus 0h including many interferon (IFN)-regulated genes like IRF1, IFITM1, STAT1, JAK3 and several apoptosis related genes such as FAS and Caspase 8. The majority of these genes were at least 2-fold up-regulated at 6 hours, but most returned to pre-treatment levels by 24 hours. Thus, rituximab induced a transient gene expression signature that correlated with the cytokine release syndrome during the infusion. To determine whether or not this IFN signature was caused directly by rituximab signaling or indirectly by cytokines released during the infusion, we compared rituximab and IFN gamma effects on CLL cells in-vitro. Both rituximab (10ug/ml with cross-linking) and IFN-gamma (1000U/ml) induced FAS (CD95) expression in CLL cells measured by flow cytometry. CD95 expression was low on untreated CLL cells, at 6 hours, up-regulation of CD95 expression with rituximab was stronger than with IFN, while at 24 hours, IFN treated cells showed slightly higher CD95 expression. Next, we investigated whether rituximab is able to activate STAT1, the main transcription factor regulating IFN target genes. IFN gamma induced rapid phosphorylation of STAT1 in CLL cells, but rituximab did not. However, we observed phosphorylation of ERK in response to rituximab as has been reported by others. After in-vitro stimulation with rituximab and IFN-gamma, IRF-1 and STAT-1 were up-regulated at 2 and 6 hours as measured by real time PCR, albeit with a stronger response after IFN. We conclude that rituximab is associated with a specific gene expression signature in CLL patients that is characterized by IFN response genes. At this point, we cannot rule out that this signature is contributed in part by cytokines released during the rituximab infusion. However, the rapid up-regulation of CD95, STAT1, and IRF1 under controlled in-vitro conditions is consistent with a direct effect of rituximab. Ongoing studies aim to better characterize rituximab signaling in CLL and to determine whether this can contribute to apoptosis or sensitize the leukemic cells to chemotherapy.
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Bennett, Lynda, A. Karolina Palucka, Edsel Arce, Victoria Cantrell, Josef Borvak, Jacques Banchereau, and Virginia Pascual. "Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus Blood." Journal of Experimental Medicine 197, no. 6 (March 17, 2003): 711–23. http://dx.doi.org/10.1084/jem.20021553.
Повний текст джерелаАнотація:
Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
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Patiño-Trives, A. M., C. Perez-Sanchez, A. Ibañez-Costa, M. Luque-Tévar, M. D. C. Abalos-Aguilera, I. Arias de la Rosa, D. Ruiz, et al. "POS0419 ABERRANT SPLICEOSOME AND ALTERED EXPRESSION OF IFN-RESPONSE RELATED GENES ARE HALLMARKS OF MONOCYTES FROM LUPUS PATIENTS WITH RENAL DISEASE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 438.2–439. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2534.
Повний текст джерелаАнотація:
Background:To date, novel mechanisms such as the involvement of splicing machinery components in lupus nephropathy and its interplay with the transcriptome in innate immune cells have not been evaluated.Objectives:1- To identify altered transcriptomic signatures associated with the immune response of monocytes from SLE patients and its association with clinical features. 2- To evaluate the role of the spliceosome linked to the transcriptomic profile of SLE monocytes. 3- To analyze mechanistically the impact of anti-dsDNA antibodies (Ab) and the modulation of the spliceosome in the SLE monocytes activity.Methods:Sixty SLE patients and forty healthy donors (HD) were included in the study. Infiltration rate of myeloid cells and its association with clinical features were analyzed in kidney biopsies by Immunohistochemistry. In parallel, circulating monocytes were purified from peripheral blood by immune-magnetic selection. The expression of a set of 770 genes related to autoimmune/inflammatory diseases was evaluated using NanoString Technologies. The levels of the main 45 components of the splicing machinery were further analyzed in these samples using a microfluidic qPCR array (Fluidigm). An extensive clinical/serological evaluation was also performed, comprising disease activity, renal involvement parameters, autoAb profile, and the systemic inflammatory status (27-plex Assay). Finally, in vitro studies involving anti-dsDNA-IgG Ab treatment and over/down-expression of splicing machinery components were carried out to analyze their effects in the monocyte activity.Results:Infiltration of CD68 expressing cells was confirmed in kidney biopsies and associated with parameters of kidney failure (C3/C4, chronic index), highlighting the key role of the myeloid compartment in lupus nephropathy. Gene expression profiling recognized 156 genes differentially expressed in SLE monocytes compared with HDs, including 87 genes up-regulated and 69 down-regulated. Functional analysis showed that most dysregulated genes were associated with the IFN response (i.e. IFIT1, IFI44, IFI44L, RSAD2). In parallel, the altered expression of 27 spliceosome components was demonstrated in SLE monocytes compared with HD, including 3 up-regulated and 24 down-regulated. Correlation studies demonstrated that the aberrant expression of splicing machinery components was linked to the altered interferon signature and the plasma inflammatory profile. This aberrant profile at molecular level was associated with the disease activity status, anti-dsDNA positivity and C3/C4 levels. Interestingly, SLE patients with renal disease displayed a simultaneous alteration of both, the IFN and the spliceosome signatures in monocytes, along with an enlarged pro-inflammatory profile in plasma. Logistic regression models that integrated the concomitant alteration of some splicing machinery components and IFNs genes identified lupus nephritis patients with high accuracy. Mechanistic studies showed that in vitro treatment of monocytes from HDs with anti-dsDNA promoted a concomitant deregulation of the IFN signature and the expression of several spliceosome components (i.e. PTB, RBM17, RNU6ATAC). Finally, the over/down-expression of selected spliceosome components (PTB and RBM17) in monocytes from SLE patients reduced the active release of inflammatory cytokines and their adhesion capacity.Conclusion:1) Monocytes from SLE patients with renal involvement exhibit a remarkable alteration of genes associated with the IFN response, further linked with the aberrant expression of several splicing machinery components. 2) Anti-dsDNA promoted the dysregulation in monocytes of both the IFN and spliceosome signatures, along with an active release of pro-inflammatory mediators. 3) The modulation of key splicing components in monocytes from SLE patients reduce their pro-inflammatory status and migration capacity. Ongoing studies may provide novel biomarkers and therapeutic tools to treat lupus nephropathy.Acknowledgements:Funded by ISCIII, PI18/00837 and RIER RD16/0012/0015 co-funded with FEDERDisclosure of Interests:None declared
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Padariya, Monikaben, Alicja Sznarkowska, Sachin Kote, Maria Gómez-Herranz, Sara Mikac, Magdalena Pilch, Javier Alfaro, Robin Fahraeus, Ted Hupp, and Umesh Kalathiya. "Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes." Biomolecules 11, no. 5 (April 22, 2021): 622. http://dx.doi.org/10.3390/biom11050622.
Повний текст джерелаАнотація:
Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.
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Murata, Hisashi, Makoto Kinoshita, Yoshiaki Yasumizu, Daisuke Motooka, Shohei Beppu, Naoyuki Shiraishi, Yasuko Sugiyama, et al. "Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder." Neurology - Neuroimmunology Neuroinflammation 9, no. 3 (February 24, 2022): e1149. http://dx.doi.org/10.1212/nxi.0000000000001149.
Повний текст джерелаАнотація:
Background and ObjectivesRecently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated.MethodsClinical samples were obtained from 32 patients with aquaporin-4 antibody–positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed.ResultsEnhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed.DiscussionOur study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.
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Aue, A., F. Szelinski, S. Weißenberg, A. Wiedemann, T. Rose, A. Lino, and T. Dörner. "OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 4–5. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2955.
Повний текст джерелаАнотація:
Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen
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Reijers, Irene L. M., Petros Dimitriadis, Elisa A. Rozeman, Judith M. Versluis, Annegien Broeks, Linda J. W. Bosch, Jasper Bouwman, et al. "Personalized combination of neoadjuvant domatinostat, nivolumab and ipilimumab in macroscopic stage III melanoma patients stratified according to the interferon-gamma signature: The DONIMI study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS10087. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps10087.
Повний текст джерелаАнотація:
TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.
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Wang, Wei, Congrong Xu, Yan Ren, Shiwei Wang, Chunli Liao, Xiaoyan Fu, and Haixia Hu. "A Novel Cancer Stemness-Related Signature for Predicting Prognosis in Patients with Colon Adenocarcinoma." Stem Cells International 2021 (October 15, 2021): 1–23. http://dx.doi.org/10.1155/2021/7036059.
Повний текст джерелаАнотація:
Objective. To explore the cancer stemness features and develop a novel cancer stemness-related prognostic signature for colon adenocarcinoma (COAD). Methods. We downloaded the mRNA expression data and clinical data of COAD from TCGA database and GEO database. Stemness index, mRNAsi, was utilized to investigate cancer stemness features. Weighted gene coexpression network analysis (WGCNA) was used to identify cancer stemness-related genes. Univariate and multivariate Cox regression analyses were applied to construct a prognostic risk cancer stemness-related signature. We then performed internal and external validation. The relationship between cancer stemness and COAD immune microenvironment was investigated. Results. COAD patients with higher mRNAsi score or EREG-mRNAsi score have significant longer overall survival (OS). We identified 483 differently expressed genes (DEGs) between the high and low mRNAsi score groups. We developed a cancer stemness-related signature using fifteen genes (including RAB31, COL6A3, COL5A2, CCDC80, ADAM12, VGLL3, ECM2, POSTN, DPYSL3, PCDH7, CRISPLD2, COLEC12, NRP2, ISLR, and CCDC8) for prognosis prediction of COAD. Low-risk score was associated with significantly preferable OS in comparison with high-risk score, and the area under the ROC curve (AUC) for OS prediction was 0.705. The prognostic signature was an independent predictor for OS of COAD. Macrophages, mast cells, and T helper cells were the vital infiltration immune cells, and APC costimulation and type II IFN response were the vital immune pathways in COAD. Conclusions. We developed and validated a novel cancer stemness-related prognostic signature for COAD, which would contribute to understanding of molecular mechanism in COAD.
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Amorim, Camila Farias, Brukawit A. Goshu, Cláudia Lombana, Fernanda O. Novais, Ba T. Nguyen, Lucas P. Carvalho, Edgar M. Carvalho, Daniel P. Beiting, and Phillip Scott. "A systemic inflammatory response primes blood monocytes in cutaneous leishmaniasis." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 99.15. http://dx.doi.org/10.4049/jimmunol.206.supp.99.15.
Повний текст джерелаАнотація:
Abstract Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-y within lesions. Phagocytic cells recruited to lesions are exposed to IFN-y which triggers their ability to kill the intracellular parasites. To determine what systemic responses are occurring that might influence the disease, we performed RNA sequencing (RNA-seq) on the blood of 50 L. braziliensis-infected patients, as well as 14 healthy controls. Genes reflecting Interferon downstream activation such as GBP1-6, STAT1, IDO1, AIM2, BATF2, SOCS1 and FCGR-related genes, were upregulated in patients and functional enrichment analysis identified a transcriptional type II Interferon-stimulated gene (ISG) signature as the dominant response. An increase in monocytes and macrophages in the blood, estimated from our RNA-seq dataset, was positively correlated with this type II ISG signature. Consistent with this result, patients had circulating IFN-y in their serum. Monocytes in the bone marrow and circulating in the blood of mice infected with leishmania exhibited increased expression of Class II, further supporting the premise that there is a systemic response to infection. Together, these results suggest that there is a mechanism to limit systemic spread of the parasites, as well as enhance parasite control by pre-activating cells prior to lesion entry.
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Ehrt, Sabine, Dirk Schnappinger, Stefan Bekiranov, Jörg Drenkow, Shuangping Shi, Thomas R. Gingeras, Terry Gaasterland, Gary Schoolnik та Carl Nathan. "Reprogramming of the Macrophage Transcriptome in Response to Interferon-γ and Mycobacterium tuberculosis". Journal of Experimental Medicine 194, № 8 (15 жовтня 2001): 1123–40. http://dx.doi.org/10.1084/jem.194.8.1123.
Повний текст джерелаАнотація:
Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-γ (IFN-γ) activates macrophages by driving Janus tyrosine kinase (JAK)/signal transducer and activator of transcription–dependent induction of transcription and PKR-dependent suppression of translation. Microarray-based experiments reported here enlarge this picture. Exposure to IFN-γ and/or Mtb led to altered expression of 25% of the monitored genome in macrophages. The number of genes suppressed by IFN-γ exceeded the number of genes induced, and much of the suppression was transcriptional. Five times as many genes related to immunity and inflammation were induced than suppressed. Mtb mimicked or synergized with IFN-γ more than antagonized its actions. Phagocytosis of nonviable Mtb or polystyrene beads affected many genes, but the transcriptional signature of macrophages infected with viable Mtb was distinct. Studies involving macrophages deficient in inducible nitric oxide synthase and/or phagocyte oxidase revealed that these two antimicrobial enzymes help orchestrate the profound transcriptional remodeling that underlies macrophage activation.
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Skov, Vibe, Caroline Riley, Mads Thomassen, Lasse Kjær, Thomas Stauffer Larsen, Ole Weis Bjerrum, Torben A. Kruse, and Hans Carl Hasselbalch. "Interferon-alfa2 Treatment of Patients with Polycythemia Vera and Related Neoplasms Influences Deregulated Inflammation and Immune Genes in Polycythemia Vera and Allied Neoplasms." Blood 132, Supplement 1 (November 29, 2018): 5490. http://dx.doi.org/10.1182/blood-2018-99-118690.
Повний текст джерелаАнотація:
Abstract Introduction: The Philadelphia-negative myeloproliferative neoplasms are associated with deregulation of inflammation and immune genes implying a gene signature of a chronic inflammatory state and immune deregulation. Several studies have demonstrated interferon-alpha2 (IFN) to be highly efficacious in normalizing elevated blood cell counts and in inducing molecular remissions as well. Using whole blood gene expression, we herein for the first time show that IFN profoundly influences the deregulated inflammation- and immune genes giving rise to a gene signature indicative of decreased inflammation and improved regulation of immune genes during IFN treatment. Material and Methods: Gene expression microarray studies have been performed on eight patients with ET, 21 patients with PV, and 4 patients with PMF. All patients received treatment with IFN, in the large majority in a dosage ranging from 45-90 ug x 1 sc/week. Gene expression profiles were generated using Affymetrix HG-U133 2.0 Plus microarrays recognizing 54.675 probe sets (38.500 genes). Total RNA was purified from whole-blood and amplified to biotin-labeled aRNA and hybridized to microarray chips. Results: We identified 6261, 10,008, and 2828 probe sets to be significantly differentially expressed in ET, PV, and PMF, respectively, during treatment with IFN (pvalue <0.05). Previously, we have found 123 inflammation and immune genes to be significantly deregulated in patients with MPN compared to healthy subjects. Here, we extend the gene list with 19 inflammation and immune genes, recently shown to be involved in other cancer. Several of these 142 genes were significantly deregulated during IFN therapy. In response to treatment with IFN, 20 genes were upregulated in ET including CX3CR1, CCL2, CCR1, CCR5, CCR7, HGF, HLA-G, IL1RN, IL10RA, PTX3, TP53, and TGFB1, and 6 genes were downregulated including MAPK1, ORM1, and IL1R1. In patients with PV, ABCF1, CCL2, CCR1, CCR2, CCR5, CCR7, CD3E, CD3G, CD4, CD40LG, CX3CR1, HLA-G, IL1RN, IL8, IL10RA, PTX3, TP53, TGFB1, TNFAIP3 were among the 32 upregulated genes, and BCL6, IL1R1, MAPK1, and ORM1 were among the 10 downregulated genes. During treatment with IFN, 11 genes were upregulated in PMF including CCL2, CCR1, CCR5, CX3CR1, IL1RN, PTX3, and TNFAIP3 and 5 genes were downregulated including BCL6, IL1R1, and ORM1. Discussion and Conclusion: Interferon-alpha2 is increasingly been recognized as a highly efficacious and promising agent in the treatment of MPNs. During recent years several studies have shown that chronic inflammation and immunoderegulation is likely involved in the pathogenesis of MPNs. Thus, elevated blood levels of circulating inflammatory cytokines have been recorded, some even having a prognostic impact and predicting imminent leukemic transformation. Chronic inflammation impairs IFN-signaling and likely therefore the efficacy of IFN in MPNs, although this notion has to be confirmed in MPNs. Immunoderegulation with defective immune surveillance may contribute to the increased risk of second cancers both before and after the MPN-diagnosis. Accordingly, there is an urgent need to explore if IFN might be able to restore deregulated inflammation and immune genes in MPNs. In this study, we have convincingly shown that several genes of significance for inflammation and immune surveillance are positively influenced by IFN treatment implying a significant downregulation of upregulated inflammation genes (e.g. BCL6, IL1R1, MAPK1, ORM1,) and a significant upregulation of downregulated immune genes (e.g. ABCF1, CCR2, CCR5, CCR7, CD3D, CD3E, CD3G, CD4, CD40LG, CXCR1, HLA-G, IL10RA, IL8, TFGB1, TNFAIP3, and TP53). Recently, we have shown significant downregulation of CCR9, CREB1, FAS, LSP1, LTB, NFKB1, SCYE1, SELPG, STAT3, and TNFAIP8L1, and significant upregulation of CCL25, CCL7, CSF3, CXCL9, FOXP3, IL17A, IL17C, IL1F10, IL1F6, IL22, IL4, IL5, ITGB3, in ET, PV, and PMF compared to controls. These genes were no longer significantly deregulated during IFN-treatment. In conclusion, our results have added highly important information on the impact of IFN upon deregulated inflammation and immune genes in MPNs, thereby substantiating the beneficial effects of IFN and its major role as the cornerstone in the future treatment of MPNs. Our study opens the avenue for larger studies exploring the genomic landscape during treatment of patients with MPNs. Disclosures Hasselbalch: Novartis: Research Funding.
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Witas, Richard, Ammon B. Peck, Julian L. Ambrus, and Cuong Q. Nguyen. "Sjogren’s Syndrome and TAM Receptors: A Possible Contribution to Disease Onset." Journal of Immunology Research 2019 (May 13, 2019): 1–12. http://dx.doi.org/10.1155/2019/4813795.
Повний текст джерелаАнотація:
Sjogren’s syndrome (SS) is a chronic, progressive autoimmune disease featuring both organ-specific and systemic manifestations, the most frequent being dry mouth and dry eyes resulting from lymphocytic infiltration into the salivary and lacrimal glands. Like the related autoimmune disease systemic lupus erythematosus (SLE), SS patients and mouse models display accumulation of apoptotic cells and a Type I interferon (IFN) signature. Receptor tyrosine kinases (RTKs) of the Tyro3, Axl, and Mer (TAM) family are present on the surface of macrophages and dendritic cells and participate in phagocytosis of apoptotic cells (efferocytosis) and inhibition of Type I IFN signaling. This review examines the relationship between TAM receptor dysfunction and SS and explores the potential contributions of TAM defects on macrophages to SS development.
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Misko, Albert L., Laura D. Weinstock, Sitara B. Sankar, Amanda Furness, Yulia Grishchuk, and Levi B. Wood. "Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV." Cells 11, no. 3 (February 4, 2022): 546. http://dx.doi.org/10.3390/cells11030546.
Повний текст джерелаАнотація:
Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model. Methods: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1−/− mouse model of MLIV. Results: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Conclusions: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.
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Zhao, Yan, Dongsheng Zhang, and Yueming Sun. "Identification of a Metabolic Reprogramming-Associated Risk Model Related to Prognosis, Immune Microenvironment, and Immunotherapy of Stomach Adenocarcinoma." Journal of Oncology 2022 (September 21, 2022): 1–15. http://dx.doi.org/10.1155/2022/7248572.
Повний текст джерелаАнотація:
Stomach adenocarcinoma (STAD) is one of the most common malignant digestive tumors. Metabolic reprogramming is an essential feature of tumorigenesis. The roles of metabolic reprogramming in STAD patients were investigated to explore the tumor immune microenvironment (TME) and potential therapeutic strategies. STAD samples’ transcriptomic and clinical data were collected from The Cancer Genome Atlas (TCGA) set and the GSE84437 set. The signature based on the metabolism-related genes (MRGs) was built using the Cox regression model to predict prognosis in STAD. Notably, this MRG-based signature (MRGS) accurately predicted STAD patients’ clinical survival in multiple datasets and could serve as an indicator independently. STAD patients with high scores on the MRGS were eligible for generating a type I/II interferon (IFN) response, according to a complete examination of the link between the MRGS and TME. Tumor Immune Dysfunction and Exclusion (TIDE) and immunophenoscore (IPS) analyses revealed that STAD patients with different MRGS scores had different reactions to immunotherapy. Consequently, assessing the pattern of these MRGs increases the understanding of TME features in STAD, hence directing the development of successful immunotherapy regimens.
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Stemmer, Salomon M., Yulia Shvartser, Itay Israel Shemesh, Idit Peretz, Rinat Yerushalmi, Daniel Hendler, Izhak Haviv, Heather Ann Brauer, and Michael Castro. "Investigating the utility of breast cancer (BC) molecular signatures and immune signature profiling (ISP) as predictors of pathological complete response (pCR) to neoadjuvant chemotherapy + trastuzumab (NAC+T) in HER2+ BC." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e12109-e12109. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e12109.
Повний текст джерелаАнотація:
e12109 Background: Trastuzumab targets HER2 directly as well as contributes to activation of the immune system against the tumor. We investigated the utility of BC molecular signatures and ISP as predictors of pCR to NAC+T in HER2+ BC pts. Methods: The analysis included 73 consecutive HER2+ BC pts with pathological samples at diagnosis, who received NAC+T. RNA was extracted from 73/22 biopsy/surgical specimens (FFPE). RNA was analyzed using NanoString PanCancer Immunoncology 360 (IO360) panel with PAM50 spike-in. Raw gene counts were log2-transformed and normalized (using housekeeping genes). The analysis assessed 47 gene signatures including immune related and PAM50 signatures. Signatures were computed after removing samples with low expression of the housekeeping genes and normalization. Signature scores range from ~0 to 10 and have an average value of 5 in tumor samples from The Cancer Genome Atlas. Results: Overall, 46% of the pts achieved pCR; of 13 pts who were IHC 2+ and FISH positive, one achieved pCR. Significant associations were found between response to NAC+T (pCR, no response) and molecular signatures/ISP from the initial biopsy (Table). For pts who did not experience pCR and who underwent surgery, paired sample analysis was performed assessing molecular signatures/ISP in the initial biopsy sample vs the surgical sample. This analysis demonstrated a significant increase post-treatment (compared to the initial biopsy sample) in Risk of Recurrence (ROR) score (p=.036), interferon (IFN) downstream signature (p=.038), and antigen‐processing machinery (APM) loss (p=.002). Conclusions: Combining molecular BC signatures and ISP on biopsy samples may have a predictive value in HER2+BC pts for whom NAC+T is considered. Luminal A pts and IHC 2+ (FISH positive) are unlikely to achieve pCR with NAC+T. [Table: see text]
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Naot, Dorit, Garry A. Williams, Jian-ming Lin, Jillian Cornish, and Andrew Grey. "Evidence that Contamination by Lipopolysaccharide Confounds in Vitro Studies of Adiponectin Activity in Bone." Endocrinology 153, no. 5 (February 28, 2012): 2076–81. http://dx.doi.org/10.1210/en.2011-2004.
Повний текст джерелаАнотація:
Adiponectin, a hormone produced and secreted from adipose tissue, circulates at levels that are inversely related to visceral fat mass and bone mineral density. Adiponectin receptors are expressed in bone cells, and several studies have shown that adiponectin affects bone phenotype and might play a role in the cross talk between fat and bone tissues. In the current study, we determined global changes in gene expression induced by adiponectin in mouse bone marrow cells, in order to identify the molecular mechanisms that mediate adiponectin's effect to inhibit osteoclast differentiation in these cultures. The gene signature that was produced by microarray analysis was very similar to a signature produced by activation of type I interferons (IFN), and we therefore tested the hypothesis that the adiponectin preparation, although marketed as “lipopolysaccharide (LPS) free”, was contaminated with LPS that induced an IFN response in the bone marrow cells. Heat inactivation of the adiponectin preparation and the use of small interfering RNA to knockdown the AdipoR1 receptor had not diminished the activity of the adiponectin preparation to induce the IFN target genes Ccl5 and Irf7. Thus, the changes in gene expression determined in the bone marrow cultures are likely to be the result of a combination of adiponectin and LPS effects. Our study suggests that the purity of commercially available proteins needs to be verified and that experimental results of adiponectin activity in vitro should be interpreted cautiously.
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Canaday, David H., Naa Ayele Amponsah, and Lakshmi Ramachandra. "Geriatric adults have a significant defect in interferon-alpha production in response to influenza (133.50)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 133.50. http://dx.doi.org/10.4049/jimmunol.182.supp.133.50.
Повний текст джерелаАнотація:
Abstract Ninety percent of deaths attributed to influenza are in the elderly. While age-related decline in T cell function has been demonstrated, much less is known about the innate immune responses during natural infection and vaccination that shape humoral and cell mediated responses. We analyzed interferon alpha (IFN-alpha) production in peripheral blood mononuclear cells (PBMCs) isolated from younger adult and geriatric individuals that were stimulated with influenza or TLR ligands. A majority of geriatric PBMCs made significantly lower amounts of IFN-alpha, a signature anti-viral cytokine, in response to influenza. Surprisingly, geriatric PBMCs had normal production of IFN-alpha in response to the TLR9 ligand, CpG ODN, and the TLR7 ligand, guardiquimod. We determined that plasmacytoid dendritic cells (pDCs) are the main producers of IFN-alpha in response to influenza, CpG ODN and guardiquimod in PBMCs by cell depletion studies, and that influenza signals through TLR7. We are currently investigating the mechanism for this defect in IFN-alpha production in response to influenza by geriatric pDCs. A better understanding of the specific innate immune responses to influenza in geriatric individuals may allow a better understanding of the pathophysiology of the host-influenza interaction and therefore allow a more targeted approach to vaccine design. This work is supported by AI077056 and AI36219.
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Lee, Keun-Wook, Young Suk Park, Joong Bae Ahn, Jin Kyung Lee, Jiyeon Ryu, Bitna Oh, Chan-Young Ock та ін. "332 Novel TGF-β signatures in metastatic colorectal cancer patients treated with vactosertib in combination with pembrolizumab". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (листопад 2020): A358. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0332.
Повний текст джерелаАнотація:
BackgroundDual inhibition of transforming growth factor beta (TGF-β) signaling and PD-1 is a promising strategy to reverse immunosuppressive tumor microenvironment and poor responses to immunotherapy. Based on preliminary clinical data with vactosertib, a highly selective and potent inhibitor of TGF-β receptor type 1, in combination with pembrolizumab, this study aimed to explore a biomarker with predictive value for this regimen in metastatic microsatellite stable (MSS) colorectal cancer (CRC).MethodsTumor biopsy samples were obtained from 24 CRC patients at baseline and cycle 2 in the ongoing MP-VAC-204 study and analyzed by RNAseq and DNAseq. Consensus molecular subtype (CMS), TGF-β responsive gene signatures, IFN-γ signatures, and tumor mutation burden (TMB) were analyzed. Clinically benefited patients were defined by those who achieved objective response assessed by RECIST v1.1/iRECIST or progression free survival more than 24 weeks. Vactosertib responsive gene signature (VRGS) that showed significantly different expression among previously identified TGF-β responsive gene signature and IFN-γ signature in responders than in non-responders was identified and VRGS score was calculated by a mean value of VRGS filtered-in gene expressions divided by 6 house-keeping gene expressions.ResultsAs of July 1, 2020, of the total evaluable 24 patients, 71% were CMS4 subtype and 33% were with high TMB (≥10 mut/Mb). Clinical benefit rate was 33.3% including 3 PR and 1 iPR patients. No significant associations in response rate were observed with CMS subtypes or TMB status. VRGS score was significantly enriched in responders than in non-responders (P value = 0.006; AUC = 0.836). A preliminary cut-off value of 2.179 resulted in 94% specificity and 75% sensitivity with 85.7% patients correctly classifying as a responder. After treatment of vactosertib plus pembrolizumab, TGF-β-related VRGS was significantly decreased and the extent of decrease was greater in responders, compared to non-responders.Ethics ApprovalThe study was approved by Ethics Board of Asan Medical Center, Yonsei University College of Medicine, Samsung Medical Center, and Seoul National University Bundang Hospital with approval number 2018-1215, 4-2018-0728, SMC 2018-07-146-006, and B-1808/487-003, respectively.ConclusionsDevelopment of VRGS as a predictive biomarker for this combination treatment with vactosertib and pembrolizumab is ongoing and its potential clinical utility for patient selection will be explored.Trial RegistrationNCT03724851
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Yamashita, Nami, Atsushi Fushimi, Yoshihiro Morimoto, Atrayee Bhattacharya, Masayuki Hagiwara, Masaaki Yamamoto, Tsuyoshi Hata, et al. "Targeting MUC1-C Suppresses Chronic Activation of Cytosolic Nucleotide Receptors and STING in Triple-Negative Breast Cancer." Cancers 14, no. 11 (May 24, 2022): 2580. http://dx.doi.org/10.3390/cancers14112580.
Повний текст джерелаАнотація:
The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression of the RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) and the cGAS-stimulator of IFN genes (STING) in triple-negative breast cancer (TNBC) cells. Consistent with inducing the PRR/STING axis, MUC1-C drives chronic IFN-β production and activation of the type I interferon (IFN) pathway. MUC1-C thereby induces the IFN-related DNA damage resistance gene signature (IRDS), which includes ISG15, in linking chronic inflammation with DNA damage resistance. Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody–drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development.
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Lin, Jamie, Amanda Tchakarov, Noha Abdel-Wahab, Houssein Safa, Salah-Eddine Bentebibel, Maen Abdelrahim, Cassian Yee, Adi Diab, and Ala Abudayyeh. "808 Tertiary lymphoid structure gene signature detected in immune checkpoint inhibitor-associated renal immune related adverse event." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A845. http://dx.doi.org/10.1136/jitc-2021-sitc2021.808.
Повний текст джерелаАнотація:
BackgroundTertiary lymphoid structures (TLSs) have been previously associated with ICI induced response in patients with cancer, but a commensurate observation has not been made in ICI associated immune related adverse events (irAEs). Acute interstitial nephritis (AIN) is the predominant lesion reported in patients with renal irAEs, but various etiologies can also trigger the development of AIN including non-ICI drugs (e.g. non-steroidal anti-inflammatory drugs, antibiotics, proton pump inhibitors, etc.), and it is unknown whether these mechanisms are similar. With increasing indications for ICIs in cancer therapy, there is a critical need to define immune pathways driving the emergence of irAEs. To address this critical knowledge gap, we performed gene expression profiling on ICI-AIN, drug-AIN, and control (non-AIN) kidney biopsy specimens.MethodsTotal RNA extracted from ICI-AIN (n = 6), drug-AIN (n = 4), and control (n = 4) fixed formalin paraffin embedded archival kidney biopsy samples was analyzed by Nanostring nCounter PanCancer Immune Profiling Panel using NanoString nCounter FLEX Analysis System.ResultsThree comparisons were conducted: ICI-AIN vs control, drug-AIN vs control, and ICI-AIN vs drug-AIN. A total of 147 genes were differentially expressed in ICI-AIN vs control and the most differentially expressed genes were CXCL 9, 10, and 11. Similarly, cell marker gene expression signatures (GES) revealed significant upregulation of T and B cell markers in ICI-AIN vs control (P < 0.01) and ICI-AIN vs drug-AIN (T cell P < 0.05; B cell P < 0.01). Differences in T and B cell score were not detected in drug-AIN vs control. Since irAEs have been associated with anti-tumor efficacy, we investigated whether a TLS signature could be detected in ICI-AIN using a four GES (CD79A, MS4A1, LAMP3 and POU2AF1). The ICI-AIN group had significantly higher TLS score compared to both control and drug-AIN groups. Since several TLS signatures have been reported, we also calculated a 12-chemokine TLS GES which was also found to be statistically significant (P < 0.05). Th1 and Th17 cells have been associated with the formation of TLS, differential upregulation of Th1 associated genes but not Th17 associated genes were detected. Furthermore, differential expression IFN-y and TNF signature was also observed in ICI-AIN group.ConclusionsThis study is the first to demonstrate the presence of TLS immune signature in irAEs. Further investigations into the prognostic significance and strategies to uncouple ICI-associated anti-tumor benefits from ICI-induced irAEs should be explored.Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition's Ethics Board, approval number PA16-1016
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Reijers, ILM, EA Rozeman, P. Dimitriadis, O. Krijgsman, LJW Bosch, S. Cornelissen, J. Bouwman, et al. "P01.15 Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in macroscopic stage III melanoma patients stratified according to interferon-gamma (IFN-gamma) signature – the DONIMI study." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A15.2—A16. http://dx.doi.org/10.1136/jitc-2020-itoc7.28.
Повний текст джерелаАнотація:
BackgroundThe previous OpACIN and OpACIN-neo studies investigating neoadjuvant IPI plus NIVO have demonstrated high pathologic response rates (74–78%) and favorable long-term outcomes for patients (pts) with a pathological response; at 36 and 18 months follow up only 1/71 (1.4%) responders has relapsed. In contrast, pathological non-responders have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline IFN-γ signature high pts were more likely to respond to IPI plus NIVO. The DONIMI study tests the combination of NIVO ± IPI combined with a class 1 histone deacetylase inhibitor, domatinostat (DOM), according to the pts IFN-γ signature. We have developed a neoadjuvant IFN-γ signature, based on the signature previously described by Ayers et al., that will be used for the first time to classify pts in this prospective trial.Trial designThis two-center investigator-initiated phase 1b study aims to assess the safety and feasibility of neoadjuvant NIVO ± DOM ± IPI in 45 stage III melanoma pts with macroscopic de-novo or recurrent disease. IFN-γ signature high pts (n=20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240 mg q3wk) or Arm B (2 cycles NIVO 240 mg q3wk + DOM 200 mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n=25) will be randomized to Arm C (2 cycles NIVO 240 mg q3wk + DOM 200 mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240 mg q3wk + IPI 80 mg q3wk + DOM 200 mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200 mg BID, d1-14, q3wks), a lower dosing scheme (100 mg OD, d1-14, q3wks) or the same dosing scheme (200 mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 patients cannot adhere to the planned time of surgery (week 6 ± 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. To date, 7 patients have been enrolled.Clinical trial informationNCT04133948Disclosure InformationI.L.M. Reijers: None. E.A. Rozeman: None. P. Dimitriadis: None. O. Krijgsman: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; BMS. L.J.W. Bosch: None. S. Cornelissen: None. J. Bouwman: None. J.M. Versluis: None. D. Rao: None. B. van de Wiel: None. A.J. Spillane: None. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD Oncology, Novartis, Pierre Fabre, Roche. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD, Merck, Merck-Pfizer, 4SC. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, Nanostring. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab, Pierre Fabre.
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Vadakekolathu, Jayakumar, Tung On Yau, Heidi Altmann, Sarah E. Church, Hanna A. Knaus, Mark D. Minden, Jan K. Davidson-Moncada, et al. "An Immune Senescence and Exhaustion-Related RNA Profile Predicts Clinical Outcomes in Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-134779.
Повний текст джерелаАнотація:
Background Chemotherapy refractoriness and disease relapse continue to be significant obstacles to therapeutic success in AML. We have recently identified bone marrow (BM) transcriptomic profiles that stratify patients with AML into an immune-infiltrated and an immune-depleted subtype and that refine the accuracy of survival prediction in response to conventional chemotherapy beyond that afforded by cytogenetic and molecular prognosticators (Vadakekolathu J, et al. Sci. Transl. Med. 2020; 12: eaaz0463). Importantly, AML CD8+ T cells exhibit features of immune exhaustion and senescence (IES), including the upregulation of natural killer (NK) cell-associated transcripts, which persist only in chemotherapy non-responders (Knaus HA, et al. JCI Insight 2018; 3: e120974). The aim of the current study was to determine whether IES correlate with immune infiltration and with clinical outcomes in AML. Methods We used prior knowledge and gene set enrichment analysis (GSEA) to derive a 68-gene IES signature score (computed as the cohort-wide average of gene expression) from publicly available RNA-sequencing datasets (TCGA and Beat-AML Master Trial; 162 and 281 AML patients, respectively). The wet-lab AML cohorts used in this study included a total of 382 BM samples from children and adults with AML treated with curative intent. BMs were collected at time of diagnosis, complete remission (CR) and relapse (PMCC, SAL and CHOP series). BM RNAs were profiled on the nCounter platform using the PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA). Results In the AML discovery cohort, the IES score significantly correlated with BM lymphoid infiltration (R=0.958) and with CD8+ T cell (R=0.88), cytotoxic T cell (R=0.90) and tumor inflammation signature scores (R=0.82, P<0.0001 for all; Fig. 1A). The novel IES gene signature showed minimal overlap with previously discovered interferon (IFN)-related gene sets with prognostic relevance in AML (Fig. 1B) and was higher in TP53-mutated (P<0.0001) and RUNX1-mutated (P=0.0071) compared with WT AML. Overall survival (OS) was significantly shorter in patients with higher than median IES scores (Fig. 1C). IES signature scores were also associated with worse clinical outcomes in Beat-AML cases (median OS of 10.6 and 21.1 months, respectively, in patients with higher and lower than median IES scores; Fig. 1D) and were higher in primary induction failures (PIF) compared with chemotherapy responders (Fig. 1E). The top IES genes associated with survival prediction both in TCGA and Beat-AML, although not overlapping with published IFN-related gene sets, were still significantly enriched in type I/II IFN signaling pathways and in molecular functions indicative of heightened ion-gated channel activity, as shown by protein-protein interaction network analyses. The above findings were validated in independent wet-lab cohorts comprising adults (PMCC series; n=290; SAL series; n=46) and children (CHOP series; n=46) with AML. In the ELN adverse risk subgroup (PMCC cohort), both relapse-free survival (RFS) and OS were significantly shorter in patients with higher than median compared with lower than median IES scores (median RFS time of 6.93 versus not reached [log-rank P=0.0053], and median OS of 10.5 months versus 18 months [log-rank P=0.0011], respectively). In contrast, the IES signature score failed to stratify survival in patients with ELN favorable and intermediate risk. Finally, a pairwise comparison of matched diagnostic, CR and relapse BM samples (SAL series; n=22 patients and CHOP series; n=46 patients) showed significantly higher IES signature scores at time of CR, congruent with chemotherapy-induced acceleration of IES, and at time of post-chemotherapy relapse compared with disease onset (Fig. 1F). Notably, CD8A, TBX21, a Th1 transcription factor, and markers of NK cells and cytotoxic T lymphocytes, including KLRK1, KLRD1, KLRC2, GNLY, and granzymes, were among the top ranked immune genes associated with AML relapse (Fig. 1G). Conclusions Patients with immune-infiltrated AML exhibit features of IES, which may correlate with adverse-risk molecular features, chemotherapy refractoriness and shorter survival. Molecular circuits reflective of IES might also underpin AML relapse after conventional induction chemotherapy. IES T cells could be functionally rejuvenated by novel immunotherapies being investigated in AML. Figure 1 Disclosures Church: NanoString Technologies, Inc.: Current Employment. Davidson-Moncada:Macrogenics: Current Employment. Tasian:Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Gojo:Amphivena: Research Funding; Merck: Research Funding; Genentech: Research Funding; Amgen: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Rutella:Kura Oncology: Research Funding; MacroGenics, Inc.: Research Funding; NanoString Technologies, Inc.: Research Funding.
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Guo, Ya, Yin Bin Zhang, Yi Li, Wang Hui Su, Shan He, Shu Pei Pan, Kun Xu, and Wei Hua Kou. "Three Prognostic Biomarkers Correlate with Immune Checkpoint Blockade Response in Bladder Urothelial Carcinoma." International Journal of Genomics 2022 (May 26, 2022): 1–35. http://dx.doi.org/10.1155/2022/3342666.
Повний текст джерелаАнотація:
Aim. We aim to develop a signature that could accurately predict prognosis and evaluate the response to immune checkpoint blockade (ICB) in bladder urothelial carcinoma (BLCA). Methods. Based on comprehensive analysis of public database, we identified prognosis-related hub genes and investigated their predictive values for the ICB response in BLCA. Results. Among 69 common DEGs, three genes (AURKA, BIRC5, and CKS1B) were associated with poor prognosis, and which were related to histological subtypes, TP53 mutation status, and the C2 (IFN-gamma dominant) subtype. Three genes and their related risk model can effectively predict the response of immunotherapy. Their related drugs were identified through analysis of drug bank database. Conclusions. Three genes could predict prognosis and evaluate the response to ICB in BLCA.
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Wilkinson, Grey A., Aine Piar, Christopher Resnyk, M. Jordan Humphrey, Keith Glendinning, Hue Tran, Romit Chakrabarty, Andres Gutierrez, and Matthew C. Coffey. "Pelareorep to promote the expression of a IFN-gamma-related gene signature that predicts response to checkpoint blockade therapy." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 3089. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.3089.
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Yu, Yunfang, Wenda Zhang, Qiyun Ou, Anlin Li, Yongjian Chen, Ying Wang, Jianli Zhao, Yujie Tan, and Herui Yao. "Development and validation of novel microenvironment-based immune molecular subtypes of breast cancer: Implications for immunotherapy." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1094. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1094.
Повний текст джерелаАнотація:
1094 Background: Breast cancer treatment with immunotherapy can improve clinical benefits, but the majority of patients did not respond to the treatment. To understand tumor–immune interactions in breast cancer, we identified novel microenvironment-based immune molecular subtypes. Methods: A training cohort of 1,394 breast cancer patients from the Molecular Taxonomy of Breast Cancer International Consortium profiled by RNA and DNA sequencing data were analyzed to calculate immune-related gene biomarkers and to assign prognostic categories using LASSO Cox regression model. Additionally, 969 patients from The Cancer Genome Atlas data set was used as an independent validation cohort. We further compared tumor mutation burden (TMB) and cytolytic activity (CYT) levels between different immune molecular subtypes. Results: Using the LASSO model, we established an immune molecular classifier based on following 5 features: IFN-γ signature, ICOSLG, TNFRSF14, Mast.cells.resting, and T.cells. CD4.memory.resting. Then we found that it contained two distinct microenvironment-based subtypes (immune class and non-immune class), characterized by significant differences in overall survival in the training cohort (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.61 to 0.81; P < 0.001) and in the validation cohort (HR 0.34; 95% CI 0.22 to 0.54; P < 0.001). We found an inverse association between immune gene expression and TMB levels (ρ = 0.096, P < 0.001). Immune class subtype patients with good prognosis had significantly lower TMB and higher CYT than did non-immune class subtype patients with poor prognosis (all, P < 0.05). The clinical use of the immune molecular subtypes showed a closer association with survival than did IFN-γ signature or PD-L1 expression (all, P < 0.05). The robustness of the immune molecular subtypes was confirmed in the validation cohort. Conclusions: We revealed novel immune molecular subtypes, which represented better utility in predicting breast cancer patients’ survival compared with IFN-γ signature or PD-L1, and could be an important guide for precision immunotherapy.
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Kyalwazi, Beverly, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, et al. "Abstract GS4-02: Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial." Cancer Research 82, no. 4_Supplement (February 15, 2022): GS4–02—GS4–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-gs4-02.
Повний текст джерелаАнотація:
Abstract Background Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL. Methods Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype. Results Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007). Conclusion Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate. Citation Format: Beverly Kyalwazi, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, Erin Ellis, Kathy Albain, Anne Blaes, Barbara Haley, Judy Boughey, Anthony Elias, Amy Clark, Claudine Isaacs, Rita Nanda, Hyo Han, Rachel Yung, Debu Tripathy, Kristen Edmiston, Rebecca Viscusi, Donald Northfelt, Qamar Khan, Ashish Sanil, Scott Berry, Smita Asare, Amy Wilson, Gillian Hirst, Nola Hylton, Michelle Melisko, Jane Perlmutter, Hope Rugo, Fraser Symmans, Laura van ‘t Veer, Donald Berry, Laura Esserman. Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-02.
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Ritter, J., F. Szelinski, A. Aue, A. L. Stefanski, E. Schrezenmeier, and T. Dörner. "POS0452 ABNORMALITY OF TYPE I INTERFERON SIGNALLING IN B CELLS IN PRIMARY SJÖGREN´S SYNDROME AND THE IMPACT ON LABORATORY AND CLINICAL FINDINGS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 480.1–480. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1047.
Повний текст джерелаАнотація:
BackgroundB cell hyperactivity (1), autoantibody production (anti-SS-A, anti-SS-B) and hypergammaglobulinaemia as well as interferon (IFN) signature (2) play a central role in the pathogenesis of primary Sjögren´s Syndrome (pSS). The link between these hallmarks is still elusive. While treatment of pSS remains limited, an improved understanding of IFN and JAK/STAT signalling on B cells may hold promise to improve potential treatment targets and related biomarkers.ObjectivesTo investigate downstream molecules of the IFN signalling pathway on B cells and their clinical impact in pSS.MethodsPeripheral blood from 47 pSS patients and 36 matched healthy controls (HC) was obtained and permeabilized for intracellular staining. Here B and T cell markers were applied together with Signal Transducers and Activators of Transcription 1 (STAT1), STAT2, pSTAT1 and 2, Interferon Regulatory factor 9 (IRF9), IRF7 and IRF1 and analysed by using flow cytometry. Cell subsets and correlations with all markers and clinical information were subjected to statistical analyses.ResultsCompared to HC the pSS group showed significantly elevated STAT1 expression among all B cell subsets (p>0.0001) including naïve (CD27-IgD+), pre-switched (CD27+ IgD+), switched-memory (CD27+IgD-), double negative (CD27- IgD-) B cells and plasmablasts (CD27++ CD38++). Furthermore, IRF9 and STAT2 were increased among most B cell subsets.Positive correlations were found between STAT1 and IRF9 with Siglec-1 (CD169), an IFN signature marker expressed on the surface of CD14+ monocytes (p>0.0001; r=0.633). Notably, increased levels of IRF9 positively correlates with STAT1.Upregulated STAT1 and IRF9 within pSS B cells were associated to extraglandular manifestations, high anti-SS-A and anti-SS-B autoantibodies, high anti-nuclear antibody titers (ANA) and rheumatoid factors (IgA, IgM) in pSS patients.Patients treated with prednisolone showed dose dependent inverse correlations of IRF9 expression among naïve-, memory-, and double negative B cells suggesting its treatment responsiveness.ConclusionThe current data provide evidence of type I IFN on B cell subsets in pSS. Elevated STAT1, STAT2 and IRF9 expression suggest transcriptionally activity, which was evident in patients with extraglandular manifestations and elevated serologic activity.Targeting JAK/STAT in pSS could be beneficial for patients with high STAT1 levels leading to a personalized approach for this specific subgroup of patients.References[1]Nocturne G, Mariette X. B cells in the pathogenesis of primary Sjögren syndrome. Nature Reviews Rheumatology. 2018;14(3):133-45.[2]Brkic Z, Maria NI, Helden-Meeuwsen CGv, Merwe JPvd, Daele PLv, Dalm VA, et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren’s syndrome and association with disease activity and BAFF gene expression. Annals of the Rheumatic Diseases. 2013;72(5):728-35.Disclosure of InterestsNone declared.
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Zhang, Jinfeng, Xuedi Cheng, Junzheng Wang, Yongjie Huang, Junhui Yuan, and Dawen Guo. "Gene signature and prognostic merit of M6a regulators in colorectal cancer." Experimental Biology and Medicine 245, no. 15 (June 30, 2020): 1344–54. http://dx.doi.org/10.1177/1535370220936145.
Повний текст джерелаАнотація:
Although new diagnostic techniques and treatments are increasingly updated, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to evaluate gene signature and prognostic ability of N6-methyladenosine in CRC. We used the gene expression, copy number variation, simple nucleotide variation and clinical messages from The Cancer Genome Atlas database. We first identified mutation and copy number variations of N6-methyladenosine regulatory genes in both colon adenocarcinoma and rectum adenocarcinoma. Fourteen of all 17 N6-methyladenosine regulatory genes were related with higher mRNA expression, whereas deletion leads to reduced expression. Using univariate Cox regression analysis, RBM15, YTHDC2, and METTL14 genes in the rectum adenocarcinoma samples were conspicuously associated with the prognosis of patients. Based on the least absolute shrinkage and selection operator regression models, we built a 2-gene (YTHDC2 and IGF2BP3) signature of N6-methyladenosine regulators with prognostic ability. The 1-, 3-, and 5-year AUCs of this signature were all greater than 0.6, and the P-value for risk prediction for patients was also less than 0.0001. Moreover, high IGF2BP3 gene expression was significantly associated with IFN-γ in colon adenocarcinoma , and related to the azurophil granule membrane pathway in rectum adenocarcinoma. High YTHDC2 expression in colon adenocarcinoma is closely related to cell energy metabolism. In the rectum adenocarcinoma, high YTHDC2 gene expression is related to the cell centrosome pathway. In conclusion, for the first time, we identified genetic changes of N6-methyladenosine modulators and built a prognostic gene signature in CRC. Impact statement Although new diagnostic techniques and treatments are increasingly updated for CRC, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine (m6A) as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to identify gene signature and prognostic ability of m6A modulators in CRC. For the first time, we identified genetic changes of m6A modulators and built prognostic gene signature in CRC, which may provide effective targets for the diagnosis and management of CRC.
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Furtado, Nathália Dias, Iasmim Silva de Mello, Andre Schutzer de Godoy, Gabriela Dias Noske, Glaucius Oliva, Bruno Canard, Etienne Decroly, and Myrna C. Bonaldo. "Amino Acid Polymorphisms on the Brazilian Strain of Yellow Fever Virus Methyltransferase Are Related to the Host’s Immune Evasion Mediated by Type I Interferon." Viruses 15, no. 1 (January 10, 2023): 191. http://dx.doi.org/10.3390/v15010191.
Повний текст джерелаАнотація:
Since late 2016, a yellow fever virus (YFV) variant carrying a set of nine amino acid variations has circulated in South America. Three of them were mapped on the methyltransferase (MTase) domain of viral NS5 protein. To assess whether these changes affected viral infectivity, we synthesized YFV carrying the MTase of circulating lineage as well as its isoform with the residues of the previous strains (NS5 K101R, NS5 V138I, and NS5 G173S). We observed a slight difference in viral growth properties and plaque phenotype between the two synthetic YFVs. However, the MTase polymorphisms associated with the Brazilian strain of YFV (2016–2019) confer more susceptibility to the IFN-I. In addition, in vitro MTase assay revealed that the interaction between the YFV MTase and the methyl donor molecule (SAM) is altered in the Brazilian MTase variant. Altogether, the results reported here describe that the MTase carrying the molecular signature of the Brazilian YFV circulating since 2016 might display a slight decrease in its catalytic activity but virtually no effect on viral fitness in the parameters comprised in this study. The most marked influence of these residues stands in the immune escape against the antiviral response mediated by IFN-I.
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Zheng, Mingzhu, and Jinfang Zhu. "Innate Lymphoid Cells and Intestinal Inflammatory Disorders." International Journal of Molecular Sciences 23, no. 3 (February 6, 2022): 1856. http://dx.doi.org/10.3390/ijms23031856.
Повний текст джерелаАнотація:
Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders.
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Cheng, Shun-Wen, Po-Chih Chen, Min-Hsuan Lin, Tzong-Rong Ger, Hui-Wen Chiu, and Yuan-Feng Lin. "GBP5 Repression Suppresses the Metastatic Potential and PD-L1 Expression in Triple-Negative Breast Cancer." Biomedicines 9, no. 4 (April 1, 2021): 371. http://dx.doi.org/10.3390/biomedicines9040371.
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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic progression and PD-L1 upregulation in TNBC is still largely unknown. Here, we found that guanylate binding protein 5 (GBP5) is expressed in higher levels in TNBC tissues than in non-TNBC and normal mammary tissues and serves as a poorer prognostic marker in breast cancer patients. Transwell cultivation indicated that GBP5 expression is causally related to cellular migration ability in the detected TNBC cell lines. Moreover, the computational simulation of the gene set enrichment analysis (GSEA) program against the GBP5 signature generated from its coexpression with other somatic genes in TNBC revealed that GBP5 upregulation may be associated with the activation of interferon gamma (IFN-γ)-responsive and NF-κB-related signaling cascades. In addition, we found that the coexpression of GBP5 with PD-L1 was significantly positive correlation in TNBC tissues. Robustly, our data showed that GBP5 knockdown in TNBC cells harboring a higher GBP5 level dramatically suppresses the number of migrated cells, the activity of IFN-γ/STAT1 and TNF-α/NF-κB signaling axes, and the expression of PD-L1. Importantly, the signature combining a higher GBP5 and PD-L1 level predicted the shortest time interval of brain metastasis in breast cancer patients. These findings not only uncover the oncogenic function of GBP5 but also provide a new strategy to combat metastatic/immunosuppressive TNBC by targeting GBP5 activity.
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Ben-Yehuda, Hila, Orit Matcovitch-Natan, Alexander Kertser, Amit Spinrad, Marco Prinz, Ido Amit, and Michal Schwartz. "Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress." Molecular Psychiatry 25, no. 5 (November 26, 2019): 1050–67. http://dx.doi.org/10.1038/s41380-019-0604-0.
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AbstractViral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam’s antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring’s microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn’s microglia, while systemic maternal administration of IFNβ was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring’s microglia to subsequent stress. Furthermore, maternal elevation of IFNβ resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a “two-hit” experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFNβ elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring’s programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.
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Guo, Jhe-Cyuan, Min-Shu Hsieh, Chia-Chi Lin, Ta-Chen Huang, Chun-Jung Chang та Chih-Hung Hsu. "Activated interferon-γ (IFN-γ) pathway associated with clinical benefit to programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy in esophageal squamous cell carcinoma (ESCC)." Journal of Clinical Oncology 37, № 4_suppl (1 лютого 2019): 67. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.67.
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67 Background: Previous studies indicate a preexisting T cell response and the associated “adaptive immune resistance” are critical for the clinical efficacy of anti-PD-1/PD-L1 immunotherapy. The study explored the activated IFN-γ pathway and the expression of interferon regulatory factor 1 (IRF-1), as surrogates of preexisting T cell response, as potential biomarkers associated with clinical benefit (CB) for ESCC patients receiving anti-PD-1/PD-L1 therapy. Methods: Thirty-one ESCC patients treated with PD-1/PD-L1 blockade antibody, alone or in combination, were enrolled. Tumor response evaluation was made according to Response Evaluation Criteria in Solid Tumours 1.1, and CB was defined as complete response, partial response or stable disease at least 6 months. Formalin-fixed paraffin-embedded tissues from 31 patients were analyzed for the expression of PD-L1 and IRF-1 by immunohistochemistry; 13 tissues were analyzed for the expression of immune-related genes by NanoString nCounter Human PanCancer Immune Profiling. Results: Of 31 enrolled patients (M: F= 30: 1, median age of 58), 23 and 8 were of recurrent and de novo metastatic ESCC. Sixteen and 15 received PD-1/PD-L1 blockade alone and PD-1/PD-L1-based combination therapy, respectively; 13 had received at least 2 lines of systemic therapy for advanced disease. The response rate was 10%, and the CB rate was 16%. The median progression-free-survival (PFS) and overall survival are 1.8 and 5.6 months, respectively. The 25-gene IFN-γ signature was significant higher in patients with CB than in patients without CB ( P = 0.020). Neither PD-L1 expression on tumor cells (TC) nor on immune cells (IC) was associated with CB ( P = 0.489 and 0.646, respectively). However, the IRF-1 expression on TC or on IC was significantly associated with CB ( P < 0.001 and 0.005, respectively). Conclusions: Activated IFN-γ pathway determined by 25-gene IFN-γ signature and high IHC-expression of IRF-1 were associated with CB in advanced ESCC patients receiving anti-PD-1/PD-L1-based therapy. (Supported by the grant of MOST 105-2314-B-002 -186 -MY3).
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Gan, Zhen-Shun, Qian-Qian Wang, Jia-Hui Li, Xu-Liang Wang, Yi-Zhen Wang, and Hua-Hua Du. "Iron Reduces M1 Macrophage Polarization in RAW264.7 Macrophages Associated with Inhibition of STAT1." Mediators of Inflammation 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/8570818.
Повний текст джерелаАнотація:
Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions. The aim of this study is to investigate the cross-regulatory interactions between M1 macrophage polarization and iron metabolism. Firstly, we characterized the transcription of genes related to iron homeostasis in M1 RAW264.7 macrophages stimulated by IFN-γ. The molecular signature of M1 macrophages showed high levels of iron storage (ferritin), a low level of iron export (ferroportin), and changes of iron regulators (hepcidin and transferrin receptors), which favour iron sequestration in the reticuloendothelial system and are benefit for inflammatory disorders. Then, we evaluated the effect of iron on M1 macrophage polarization. Iron significantly reduced mRNA levels of IL-6, IL-1β, TNF-α, and iNOS produced by IFN-γ-polarized M1 macrophages. Immunofluorescence analysis showed that iron also reduced iNOS production. However, iron did not compromise but enhanced the ability of M1-polarized macrophages to phagocytose FITC-dextran. Moreover, we demonstrated that STAT1 inhibition was required for reduction of iNOS and M1-related cytokines production by the present of iron. Together, these findings indicated that iron decreased polarization of M1 macrophages and inhibited the production of the proinflammatory cytokines. The results expanded our knowledge about the role of iron in macrophage polarization.
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Rutella, Sergio, Sarah E. Church, Jayakumar Vadakekolathu, Elena Viboch, Amy H. Sullivan, Tressa Hood, Sarah E. Warren, et al. "Adaptive Immune Gene Signatures Correlate with Response to Flotetuzumab, a CD123 × CD3 Bispecific Dart® Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 444. http://dx.doi.org/10.1182/blood-2018-99-111539.
Повний текст джерелаАнотація:
Abstract Background. The therapeutic approach in patients (pts) with acute myeloid leukemia (AML) has not changed substantially in >30 years. The introduction of new treatment strategies, including immunotherapy, remains a priority. Flotetuzumab, a CD123 × CD3 bispecific DART immunotherapy, is being tested in a phase 1/2 study of relapsed/refractory (R/R) AML. We previously showed that AML pts with an immune-enriched and IFN-γ-dominant tumor microenvironment (TME) experience significantly shorter relapse-free survival, suggesting refractoriness to standard induction chemotherapy (Vadakekolathu J, et al. Blood 2017; 130: 3942A). Herein, we report that an IFN-γ-dominant TME, while predicting resistance to standard therapy, is favoring response of AML to flotetuzumab. Methods. Gene expression was analyzed in 78 bone marrow (BM) samples (36 at baseline, 27 post-cycle 1 and 15 post-cycle 2) from 40 pts with relapsed or refractory AML enrolled in a phase 1/2 clinical trial of flotetuzumab (NCT#02152956). Thirty-six baseline BM samples were included in the analysis, of which 34 from pts who were treated at the target dose of ≥500 ng/kg/day. The NanoString PanCancer IO360™ assay was used to assess the expression of 770 genes, including the levels of 14 immune cell types and of 32 immuno-oncology signatures, and their correlation with response to flotetuzumab. Data are presented as score means per group±SEM and analyzed by unpaired t-test. Results. Gene expression analysis of BM samples at baseline stratifies flotetuzumab-treated pts into 3 clusters within an immunological continuum: immune-depleted, immune-exhausted and immune-enriched (Fig. 1A). Pts with primary-refractory disease (refractory to ≥2 induction attempts, first CR of <6 months, or failure after ≥4 cycles of hypomethylating agents, HMA) showed prevalently an immune-infiltrated TME phenotype, which included higher inflammatory chemokine scores compared with relapse pts (3.27±0.22 vs 2.46±0.07, p=0.026). Within this group, chemotherapy-refractory and HMA-refractory pts further stratify into immune-enriched and immune-exhausted phenotypes, respectively. Specifically, HMA-refractory pts displayed features of immune exhaustion and adaptive immune resistance, including upregulation of TIGIT (5.55±0.34 vs 3.85±0.24, p=0.006), PD-L1 (3.55±0.18 vs 2.4±0.29, p=0.009) and Treg cells (4.87±0.23 vs 3.69±0.19, p=0.0009) together with a trend toward increasingly exhausted CD8+ T cells (CD244, EOMES, LAG3 and PTGER4) compared to chemotherapy-refractory pts (Fig. 1B). Responders to flotetuzumab showed a significantly higher IFN-γ signaling scores at baseline compared to non-responders (3.31±0.32 vs 2.27±0.11, p=0.0005), consistent with the greater frequency of responders in primary refractory pts compared to relapse pts. Accordingly, baseline IFN-γ signaling scores may be predictive of response to flotetuzumab therapy (AUC=0.841; Fig. 1C). Furthermore, comparison of post-cycle 1 BM samples to baseline samples showed treatment with flotetuzumab lead to increased immune cell infiltrate and immune activation scores, as reflected by a higher Tumor Inflammation Signature (Ayers M, et al. J Clin Invest 2017; 127: 2930-40) (6.49±0.20 vs 5.93±0.12, p=0.015) together with enhanced immunoproteasome (5.72±0.07 vs 5.23±0.10, p=0.0002) and IFN-γ signaling (3.38±0.23 vs 2.53±0.14, p=0.0015) scores. Flotetuzumab-induced TME gene activation was therefore reminiscent of an immune-enrichment rather than immune-exhaustion signature. Conclusions. We provide evidence for a range of immune gene expression profiles in AML, with primary refractory pts displaying an enhanced immune infiltration signature compared with relapse pts. Furthermore, an IFN-γ-related gene signature at baseline, a feature of primary refractory pts, was associated with clinical response to flotetuzumab. HMA-refractory pts showed an immune-rich but exhausted phenotype with PD-L1 expression, suggesting these pts may further benefit from flotetuzumab combination therapy with checkpoint inhibition (Rettig M, et al. Blood 2017; 130: 1365). Lastly, treatment with flotetuzumab further shifted the immune signature toward a more immune rich phenotype. The AML TME immune gene expression can influence susceptibility to therapy, with primary refractory AML showing an IFN-γ-dominant signature associated with response to flotetuzumab. Figure Figure. Disclosures Rutella: NanoString Technologies: Research Funding. Church:NanoString Technologies: Employment. Viboch:NanoString Technologies: Employment. Sullivan:NanoString Technologies: Employment. Hood:NanoString Technologies: Employment. Warren:NanoString Technologies: Employment. Cesano:NanoString Technologies: Employment. La Motte-Mohs:MacroGenics: Employment, Equity Ownership. Muth:MacroGenics: Employment. Lelièvre:Servier: Employment. Lowenberg:Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:MacroGenics: Employment.
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Lu, Min, Seungyeul Yoo, Lijuan Xia, Xiaoli Wang, Yan Li, Jun Zhu та Ronald Hoffman. "Interferon α Has Varied Effects On CD34+ Cells From Patients With Polycythemia Vera". Blood 122, № 21 (15 листопада 2013): 2840. http://dx.doi.org/10.1182/blood.v122.21.2840.2840.
Повний текст джерелаАнотація:
Abstract Prolonged therapy with pegylated interferon a (Peg-IFNα 2a) leads to hematological and complete molecular remissions in 70% and 17% of patients with polycythemia vera (PV) , respectively (Quintas-Cardama et al, Blood 2013). We have previously shown that PV CD34+ cells are more responsive to Peg-IFNα 2a than normal CD34+ cell. The type I IFN receptor 1 and 2 were shown to be expressed by a greater number of by PV CD34+ cells than normal(N) CD34+ cells (p=0.01 and p=0.002, respectively). The effects of Peg-IFNα 2a on PV hematopoietic stem cells(HSCs) was next evaluated by incubating PV CD34+ cell for 7 days with Peg-IFNα 2a (200ng/ml) followed by their transplantation into NSG mice. The degree of human cell chimerism following the transplantation of MPN CD 34+ cells was reduced by 50 -90% and the JAK2V617F allele burden by 40 -80%. Treatment of N CD34+ cells with Peg-IFNα 2a reduced donor chimerism by only 20%. We next examined the effects of increasing doses of Peg-IFNα 2a on CD34+ cells from 11 PV patients and 5 N controls. In 4 out of 10 PV cases the IC50 of Peg-IFNα 2a was less than 200ng/ml while in the remainder of cases the IC50 was greater. Low doses of IFNa were capable of eliminating JAK2V617F+ hematopoietic colonies in these IFNα sensitive patients while higher doses of IFNα were required to achieve the same effect in the other patients. PV and N CD34+ cells were then profiled using Illumina Gene expression arrays. In total, 32 intensity data files were generated, each containing 47,231 features, corresponding to 12,388 unique genes. At p-value <0.05 386 genes were down-regulated in PV; these genes were enriched for biological processes related to immune response including the IFN-γ-mediated signaling pathway (p=0.0002), the response to IFN-gamma (p=0.004), and the cellular response to IFN-γ (p=0.0004). The 715 up-regulated genes in PV were enriched for pathways involving glycolysis (p=9.4×10-05), cellular response to stress (p=0.006), and catabolic processes. The gene expression patterns of CD34+ cells incubated with and without INFα were next analyzed. At pairwise t-test p-value <0.001, 315 genes were differentially expressed (223 up-regulated and 92 down-regulated by INFα). Up-regulated genes were enriched for INFα functions and immune response including: response to type I IFN (p=9.0×10-49), innate immune response (2.6×10-45), response to virus (7.5×10-40). Among the 223 up-regulated genes, half were previously known as IFN regulated genes (IRGs). The individual response (IR) of genes to IFN was then defined as: IRi=log (exp ressioni @IFN/exp ressioni@control) IR patterns were remarkably consistent within N samples while large inter-patient variations were observed within the PV samples. Significantly positive IRs were observed for 75 genes and negative IRs for 117 genes within PV as compared to N samples (p value<0.01). The 75 positively responsive genes to IFNa overlapped with 16 down-regulated PV signature genes (p=1.1×10-10) while the negatively responsive of genes overlapped with 41 up-regulated PV signature genes (p=2.2×10-24).These data indicate that the action of IFNa is associated with the alteration of the expression of specific PV signature genes. The varied inhibitory effect of Peg-IFNα 2a on PV colony formation was then correlated with the IR of individual genes. The IRs of OAS2 and RPS24 showed particularly high variance and were related to colony formation. OAS2 (2'-5'-oligoadenylate synthetase 2) is an INF-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response but also influences apoptosis, cell growth, differentiation and gene regulation. The IR of this gene was directly related to the inhibitory actions of IFNa (p=0.0011). By contrast, the IR of RPS24 (40S ribosomal protein S24), was inversely correlated to the IFNα response (p=0.0038). Mutations in RPS24 are associated with Diamond-Blackfan anemia. The strong correlation between the IR of these 2 genes with the inhibitory effects of IFNα suggests that their response ratio might be useful as therapeutic biomarker. These data indicate that the IFNα receptor is up-regulated in PV CD34+ cells and that IFNα treatment eliminates PV stem cells and its sensitivity against individual patient PV HSC/HPC varies. The patterns of differentially expressed genes following IFNα treatment may prove useful in determining its mechanism of action and predicting IFNα patient response. Disclosures: No relevant conflicts of interest to declare.
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Halle, Mari K., Marte Sødal, David Forsse, Hilde Engerud, Kathrine Woie, Njål G. Lura, Kari S. Wagner-Larsen, et al. "A 10-gene prognostic signature points to LIMCH1 and HLA-DQB1 as important players in aggressive cervical cancer disease." British Journal of Cancer 124, no. 10 (March 15, 2021): 1690–98. http://dx.doi.org/10.1038/s41416-021-01305-0.
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Abstract Background Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. Methods Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. Results Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). Conclusions This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.