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1
Schaller, Julien, und Judith Agudo. „Metastatic Colonization: Escaping Immune Surveillance“. Cancers 12, Nr. 11 (16.11.2020): 3385. http://dx.doi.org/10.3390/cancers12113385.
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Cancer immunotherapy has shifted the paradigm in cancer therapy by revitalizing immune responses against tumor cells. Specifically, in primary tumors cancer cells evolve in an immunosuppressive microenvironment, which protects them from immune attack. However, during tumor progression, some cancer cells leave the protective tumor mass, disseminating and seeding secondary organs. These initial disseminated tumor cells (DTCs) should potentially be susceptible to recognition by the immune system in the new host tissues. Although Natural Killer or T cells eliminate some of these DTCs, a fraction escape anti-tumor immunity and survive, thus giving rise to metastatic colonization. How DTCs interact with immune cells and the underpinnings that regulate imperfect immune responses during tumor dissemination remain poorly understood. Uncovering such mechanisms of immune evasion may contribute to the development of immunotherapy specifically targeting DTCs. Here we review current knowledge about systemic and site-specific immune-cancer crosstalk in the early steps of metastasis formation. Moreover, we highlight how conventional cancer therapies can shape the pre-metastatic niche enabling immune escape of newly arrived DTCs.
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K, Geetha, und Lisa Anna Louis. „A Rare Case of Chorioangioma / Non Immune Fetal Hydrops“. Indian Journal of Obstetrics and Gynecology 11, Nr. 3 (15.09.2023): 31–34. http://dx.doi.org/10.21088/ijog.2321.1636.11323.4.
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Chorioangioma is a placental hemangioma is a common, non-trophoblastic benign vascular placental tumour of primitive chorionic mesenchyme. The size of the tumour is important. Smaller tumours are clinically insignificant. Giant chorioangioma more than 4 cm has higher risk of maternal and foetal complications. Early diagnosis is done by imaging techniques. Placental lesions detected on sonography necessitate close surveillance of these pregnancies because of the poor outcome ofpregnancy. We present a 32-year primigravida with placental chorioangioma who went in spontaneous labour and delivered a male baby. The baby was referred to higher centre for further evaluation and revealed mild cardiomegaly. The histopathological examination of placenta helped in the diagnosis of placental chorioangioma.
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Mitra, Roshni, Sarvjeet Singh und Ashok Khar. „Antitumour immune responses“. Expert Reviews in Molecular Medicine 5, Nr. 3 (13.01.2003): 1–22. http://dx.doi.org/10.1017/s1462399403005623.
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The role of the immune system in combating tumour progression has been studied extensively. The two branches of the immune response – humoral and cell-mediated – act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells. The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells. Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance. Attempts are being made to trigger the immune system into an early and efficient response against malignant cells, and various therapeutic modalities are being developed to enhance the strength of the immune response against tumours. This review aims to elucidate the tumouricidal role of various components of the immune system, including macrophages, lymphocytes, dendritic cells and complement.
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FRIEDMANN, P. S., I. STRICKLAND, A. A. MEMON und P. M. JOHNSON. „Early time course of recruitment of immune surveillance in human skin after chemical provocation“. Clinical & Experimental Immunology 91, Nr. 3 (28.06.2008): 351–56. http://dx.doi.org/10.1111/j.1365-2249.1993.tb05908.x.
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Sopper, Sieghart, Satu Mustjoki, Angelica Loskog, Bjorn T. Gjertsen, Richard Greil, Alois Lang, Werner Linkesch et al. „Immune Monitoring In Patients With Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Treated With Frontline Nilotinib“. Blood 122, Nr. 21 (15.11.2013): 2731. http://dx.doi.org/10.1182/blood.v122.21.2731.2731.
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Background Imatinib and dasatinib modulate immune responses in vitro and in vivo. Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo. The ENEST1st study (NCT01061177) is focused on examining the role of firstline nilotinib therapy in CML-CP - this ENEST1st substudy involves a comprehensive immunological monitoring program.
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Brandlmaier, Matthias, Magdalena Hoellwerth, Peter Koelblinger, Roland Lang und Andrea Harrer. „Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation“. Cancers 16, Nr. 8 (11.04.2024): 1461. http://dx.doi.org/10.3390/cancers16081461.
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Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.
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Urie, Russell R., Chengchuan Xiao, Elizabeth Hughes, Elizabeth Lombard, Judy Chen, Aaron Morris, Diana Farris, Daniel Goldstein und Lonnie Shea. „Tissue Engineering Scaffolds Remotely Surveil Presymptomatic Allograft Rejection“. Journal of Immunology 210, Nr. 1_Supplement (01.05.2023): 173.40. http://dx.doi.org/10.4049/jimmunol.210.supp.173.40.
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Abstract As there is no assay to predict the risk of acute cellular allograft rejection (ACAR), clinicians rely on graft biopsy and aggressive, one-size-fits-all immunosuppression. Endomyocardial biopsy (EMB) is a flawed standard for heart transplant surveillance and diagnosing ACAR, as histological evidence of rejection inherently lags behind molecular biomarkers and suffers from variability. Noninvasive alternatives to EMB in ACAR surveillance, including gene profiling and donor-derived cell-free DNA, also measure lagging indicators of ACAR. A minimally invasive surveillance method is urgently needed to quantify early risk of rejection for minimizing biopsy and personalizing immunosuppression. We have developed porous biomaterial “scaffolds” for minimally-invasive sampling. These scaffolds amass immune cells producing biomarkers as an immunological niche. We identified predictive biomarkers of ACAR conserved in both in murine heterotopic heart transplant and skin transplant through the remote scaffold. We identified 43 highly differentially-expressed genes as organ-agnostic biomarkers of T cell-mediated rejection. These novel biomarkers differentiate between pre-symptomatic ACAR and recipients with healthy allografts, without invasive biopsy. Scaffold cell capture technology provides a leading indicator of ACAR by monitoring tissue-specific immune responses associated with allograft rejection. This implantable scaffold enables minimally invasive histological evaluation and molecular calculation of the early risk of rejection to reduce the frequency of routine EMB and personalize immune suppression that could prolong transplant life while minimizing risk. Supported by the Falk Medical Research Trust Catalyst Award and Transformational Award
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Bayó, Cristina, Gerhard Jung, Marta Español-Rego, Francesc Balaguer und Daniel Benitez-Ribas. „Vaccines for Non-Viral Cancer Prevention“. International Journal of Molecular Sciences 22, Nr. 20 (09.10.2021): 10900. http://dx.doi.org/10.3390/ijms222010900.
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Cancer vaccines are a type of immune therapy that seeks to modulate the host’s immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes.
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Morgado, Manuel, Ana Plácido, Sandra Morgado und Fátima Roque. „Management of the Adverse Effects of Immune Checkpoint Inhibitors“. Vaccines 8, Nr. 4 (01.10.2020): 575. http://dx.doi.org/10.3390/vaccines8040575.
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By increasing the activity of the immune system, immune checkpoint inhibitors (ICPI) can have adverse inflammatory effects, which are referred to as immune-related adverse effects (irAEs). In this review, we present the recommendations for the appropriate identification and treatment of irAEs associated with ICPI to increase the safety and effectiveness of therapy with these immuno-oncological drugs. Several guidelines to manage irAEs adopted by different American and European societies in the field of oncology were identified. A narrative review of the several strategies adopted to manage irAEs was performed. With close clinical surveillance, ICPI can be used even in patients who have mild irAEs. Moderate to severe events require early detection and appropriate treatment, particularly in patients with a history of transplantation or pre-existing autoimmune disease. In most cases, adverse reactions can be treated with the interruption of treatment and/or supportive therapy, which includes, in serious adverse reactions, the administration of immunosuppressants. The identification and treatment of irAEs in the early stages may allow patients to resume therapy with ICPI. This review is an instrument to support healthcare professionals involved in the treatment and monitoring of patients who are administered ICPI, contributing to the timely identification and management of irAEs.
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Hamatake, Kiyonori, und Kazuaki Kojima. „Initiatives for immune-related adverse events by the outpatient pharmacist clinic“. Trends in Immunotherapy 6, Nr. 1 (10.01.2022): 3. http://dx.doi.org/10.24294/ti.v6.i1.1385.
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Early detection is the key in managing side effects because immune-related adverse events (irAEs) are becoming more serious, and their onset time differs. In our hospital, we conducted an outpatient pharmacist clinic for early detection of irAEs by self-care practice for the cases of immune checkpoint inhibitor administration. As a result of a retrospective survey of 207 cases, the percentage of irAEs found by pharmacist’s suggestion of the outpatient pharmacist clinic increased over time, and a high detection ratio was obtained even for irAEs with a late onset time. The incidence of serious irAEs was higher than that in the immediate post-marketing surveillance, and different factors were considered. Although there were some problems, the outpatient pharmacist clinic had a certain effect.
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Wang, Xinlu, Melody M. H. Li, Jing Zhao, Shenglan Li, Margaret R. MacDonald, Charles M. Rice, Xiang Gao und Guangxia Gao. „Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance“. Journal of Virology 90, Nr. 22 (31.08.2016): 10247–58. http://dx.doi.org/10.1128/jvi.01487-16.
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ABSTRACTViral infection induces production of type I interferons (IFNs), which stimulate the expression of a variety of antiviral factors to inhibit viral replication. To establish effective infection, viruses need to develop strategies to evade the immune responses. A neurovirulent Sindbis virus strain with neuroinvasive properties (SVNI) causes lethal encephalitis in mice, and its replication in cultured cells is inhibited by the zinc finger antiviral protein (ZAP), a host factor that specifically inhibits the replication of certain viruses by binding to the viral mRNAs, repressing the translation of target mRNA, and promoting the degradation of target mRNA. We report here that murine embryonic fibroblast cells from ZAP knockout mice supported more efficient SVNI replication than wild-type cells. SVNI infection of 10-day-old suckling mice led to reduced survival in the knockout mice. Unexpectedly, however, SVNI infection of 23-day-old weanling mice, whose immune system is more developed than that of the suckling mice, resulted in significantly improved survival in ZAP knockout mice. Further analyses revealed that in the weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of IFN production, which restricted viral spread to the central nervous system. Blocking IFN activity through the use of receptor-neutralizing antibodies rendered knockout mice more sensitive to SVNI infection than wild-type mice. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance.IMPORTANCESindbis virus, a prototypic member of theAlphavirusgenus, has been used to study the pathogenesis of acute viral encephalitis in mice for many years. How the virus evades immune surveillance to establish effective infection is largely unknown. ZAP is a host antiviral factor that potently inhibits Sindbis virus replication in cell culture. We show here that infection of ZAP knockout suckling mice with an SVNI led to faster disease progression. However, SVNI infection of weanling mice led to slower disease progression in knockout mice. Further analyses revealed that in weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of interferon production, which restricted viral spread to the central nervous system. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance and allow enhanced neuroinvasion.
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Peng, Ling, Yongchang Zhang und Zibing Wang. „Immune Responses against Disseminated Tumor Cells“. Cancers 13, Nr. 11 (21.05.2021): 2515. http://dx.doi.org/10.3390/cancers13112515.
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Most cancer-related deaths are a consequence of metastases, a series of linear events, notably the invasion–metastasis cascade. The current understanding of cancer immune surveillance derives from studies in primary tumors, but disseminated cancer cells acquire mutations and, in some cases, appear to progress independently after spreading from primary sites. An early step in this process is micrometastatic dissemination. As such, the equilibrium between the immune system and disseminated cancer cells controls the fate of the cancer. Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients, but the efficacy of ICIs depends on both the tumor and its microenvironment. Data often suggest that disseminated cancer cells are not adequately targeted by the immune system. In this review, we summarize the main basic findings of immune responses against disseminated tumor cells and their organ-specific characteristics. Such studies may provide new directions for cancer immune therapy.
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Liu, Ping, Yan Hong, Bincai Yang, Prasha Shrestha, Nelam Sajjad und Ji-Long Chen. „Induction of the Antiviral Immune Response and Its Circumvention by Coronaviruses“. Viruses 12, Nr. 9 (18.09.2020): 1039. http://dx.doi.org/10.3390/v12091039.
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Some coronaviruses are zoonotic viruses of human and veterinary medical importance. The novel coronavirus, severe acute respiratory symptoms coronavirus 2 (SARS-CoV-2), associated with the current global pandemic, is characterized by pneumonia, lymphopenia, and a cytokine storm in humans that has caused catastrophic impacts on public health worldwide. Coronaviruses are known for their ability to evade innate immune surveillance exerted by the host during the early phase of infection. It is important to comprehensively investigate the interaction between highly pathogenic coronaviruses and their hosts. In this review, we summarize the existing knowledge about coronaviruses with a focus on antiviral immune responses in the respiratory and intestinal tracts to infection with severe coronaviruses that have caused epidemic diseases in humans and domestic animals. We emphasize, in particular, the strategies used by these coronaviruses to circumvent host immune surveillance, mainly including the hijack of antigen-presenting cells, shielding RNA intermediates in replication organelles, 2′-O-methylation modification for the evasion of RNA sensors, and blocking of interferon signaling cascades. We also provide information about the potential development of coronavirus vaccines and antiviral drugs.
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van Dommelen, Serani L. H., Hyacinth A. Tabarias, Mark J. Smyth und Mariapia A. Degli-Esposti. „Activation of Natural Killer (NK) T Cells during Murine Cytomegalovirus Infection Enhances the Antiviral Response Mediated by NK Cells“. Journal of Virology 77, Nr. 3 (01.02.2003): 1877–84. http://dx.doi.org/10.1128/jvi.77.3.1877-1884.2003.
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ABSTRACT NK1.1+ T (NKT) cells are efficient regulators of early host responses which have been shown to play a role in tumor surveillance. The relevance of NKT cells in immune surveillance of viral infections, however, is not well understood. In this study, we investigated the functional relevance of NKT cells in controlling herpesvirus infections by using challenge with murine cytomegalovirus (MCMV) as the study model. This model has proven to be one of the best systems for evaluating the role of NK cells during virus infection. Using gene-targeted mice and α-galactosylceramide (α-GalCer) as an exogenous stimulator of NKT cells, we have analyzed the role of these cells in the immune surveillance of MCMV infection. Our studies in NKT-cell-deficient, T-cell receptor Jα281 gene-targeted mice have established that classical NKT cells do not play a critical role in the early clearance of MCMV infection. Importantly, however, activation of NKT cells by α-GalCer resulted in reduced viral replication in visceral organs. Depletion studies, coupled with analysis of gene-targeted mice lacking perforin and gamma interferon (IFN-γ), have revealed that the antiviral effects of α-GalCer involve NK cells and have clearly demonstrated that the antiviral activity of α-GalCer, unlike the antitumor one, is critically dependent on both perforin and IFN-γ.
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Gasser, M., M. Grimm, E. Nichiporuk, M. Bueter, J. Lutz, T. Lebedeva, M. Koenigshausen et al. „PD-1/PDL-1 expression in colorectal cancer and its implications for tumor immune evasion“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 10046. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10046.
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10046 Background: Malignant tumors may evade immunological surveillance by an active downregulation of T cell activation by PD-1 (programmed death 1)/ PDL-1 signaling. This would result in a decreased immune response, thus, promoting tumor growth. Methods: We analyzed the expression of PD-1/PDL-1 genes, cytokines, and T cell subpopulations in tumor tissues of 81 consecutive patients who underwent surgery for primary colorectal cancer according to their UICC stage. Expression of PD-1/PDL-1, T cell subpopulations, and cytokines in tumor tissues were assessed using immunostaining, immunofluorescence, and Real Time PCR. Results: PDL-1 expression on tumor cells was significantly increased, whereas PD-1 expression on tumor cells was decreased at UICC stage III/IV. However, PD-1 expression on infiltrating CD4+ T cells was detectable in patients with advanced tumors whereas PDL-1 expression on CD4+ cells was particularly found at early stages. More regulatory T cells (CD4+CD25+CTLA-4+Foxp3+) were observed in tumors of stage III/IV patients compared to early stages. In addition, a remarkably increased amount of IL-10 was observed in the tumors of UICC III/IV patients. High expression of TGF-ß receptor II in tumors correlated with a progressive course of the disease and tumor relapses, i.e. TGF-ß RII in early tumor stages was indicative for early tumor progress. Conclusions: Our findings indicate that PDL-1 plays a key role during tumor progression and that regulatory T cells are involved in the process of evasion from immune surveillance. The elevated PDL-1 expression on T cells at early tumor stages suggests that PD1/PDL-1 interaction mediates inhibitory signals between T cells enabling the tumor to progress. PDL-1 blockade may prove to be a valuable approach for cancer immunotherapy. No significant financial relationships to disclose.
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Atif, Shaikh M., Sophie L. Gibbings, Elizabeth F. Redente, Faye A. Camp, Raul M. Torres, Ross M. Kedl, Peter M. Henson und Claudia V. Jakubzick. „Immune Surveillance by Natural IgM Is Required for Early Neoantigen Recognition and Initiation of Adaptive Immunity“. American Journal of Respiratory Cell and Molecular Biology 59, Nr. 5 (November 2018): 580–91. http://dx.doi.org/10.1165/rcmb.2018-0159oc.
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Proescholdt, Martin A., Marsha J. Merrill, Barbara Ikejiri, Stuart Walbridge, Aytac Akbasak, Steven Jacobson und Edward H. Oldfield. „Site-specific immune response to implanted gliomas“. Journal of Neurosurgery 95, Nr. 6 (Dezember 2001): 1012–19. http://dx.doi.org/10.3171/jns.2001.95.6.1012.
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Object. Immunotherapy for glioblastoma has been uniformly ineffective. The immunological environment of the brain, with its low expression of major histocompatibility complex (MHC) molecules and limited access for inflammatory cells and humoral immune effectors due to the blood—brain barrier (BBB), may contribute to the failure of immunotherapy. The authors hypothesize that brain tumors are protected from immune surveillance by an intact BBB at early stages of development. To investigate the immunological characteristics of early tumor growth, the authors compared the host response to a glioma implanted into the brain and into subcutaneous tissue. Methods. Samples of tumors growing in the brain or subcutaneously in rats were obtained for 7 consecutive days and were examined immunohistochemically for MHC Class I & II molecules, and for CD4 and CD8 lymphocyte markers. Additionally, B7-1 costimulatory molecule expression and lymphocyte-specific apoptosis were examined. Conclusions. On Days 3 and 4 after implantation, brain tumors displayed significantly lower MHC Class II expression and lymphocytic infiltration (p < 0.05). After Day 5, however, no differences were detected. The MHC Class II expressing cells within the brain tumors appeared to be infiltrating microglia. Minimal B7-1 expression combined with lymphocyte-specific apoptosis were detected in both brain and subcutaneous tumors. Low MHC Class II expression and low lymphocytic infiltration at early time points indicate the importance of the immunologically privileged status of the brain during early tumor growth. These characteristics disappeared at later time points, possibly because the increasing perturbation of the BBB alters the specific immunological environment of the brain. The lack of B7-1 expression combined with lymphocyte apoptosis indicates clonal anergy of glioma-infiltrating lymphocytes regardless of implantation site.
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Houlahan, Kathleen, Aziz Khan und Christina Curtis. „Abstract 5954: Germline epitopes modulate immune surveillance informing breast cancer subtypes“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5954. http://dx.doi.org/10.1158/1538-7445.am2023-5954.
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Abstract Cancer represents a wide spectrum of molecularly and morphologically diverse diseases. Individuals with the same histopathological classification can have tumors with drastically different molecular profiles and clinical responses to treatment. It remains unclear as to when during the disease course these differences arise and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of germline polymorphisms. It is unknown the extent to which germline differences influence the somatic evolution of a tumor. Interrogating 4,912 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in pre-invasive and invasive breast cancer. As a representative example, individuals with high burden of germline-derived epitopes in ERBB2 are significantly less likely to develop HER2+ breast cancer than ER+ or triple negative breast cancer. The same negative association between epitope burden and somatic amplification is observed for four recurrent amplicons observed in high risk ER+ breast tumors. No association was observed between somatic amplifications and epitope burden in metastatic breast cancer suggesting a subset of tumors are able to overcome immune-mediated negative selection. Tumors that do are more aggressive and demonstrate an “immune cold” phenotype. Taken together, these data show the germline genome plays a pivotal role in dictating somatic evolution in breast cancer. Exploiting germline-mediated immunoediting may facilitate the development of blood-based biomarkers that refine risk stratification within breast cancer subtypes. Citation Format: Kathleen Houlahan, Aziz Khan, Christina Curtis. Germline epitopes modulate immune surveillance informing breast cancer subtypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5954.
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Nikiforow, Sarah, Kim Bottomly und George Miller. „CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation“. Journal of Virology 75, Nr. 8 (15.04.2001): 3740–52. http://dx.doi.org/10.1128/jvi.75.8.3740-3752.2001.
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ABSTRACT In immunodeficient hosts, Epstein-Barr virus (EBV) often induces extensive B-cell lymphoproliferative disease and lymphoma. Without effective in vitro immune surveillance, B cells infected by the virus readily form immortalized cell lines. In the regression assay, memory T cells inhibit the formation of foci of EBV-transformed B cells that follows recent in vitro infection by EBV. No one has yet addressed which T cell regulates the early proliferative phase of B cells newly infected by EBV. Using new quantitative methods, we analyzed T-cell surveillance of EBV-mediated B-cell proliferation. We found that CD4+ T cells play a significant role in limiting proliferation of newly infected, activated CD23+ B cells. In the absence of T cells, EBV-infected CD23+ B cells divided rapidly during the first 3 weeks after infection. Removal of CD4+ but not CD8+ T cells also abrogated immune control. Purified CD4+ T cells eliminated outgrowth when added to EBV-infected B cells. Thus, unlike the killing of EBV-infected lymphoblastoid cell lines, in which CD8+ cytolytic T cells play an essential role, prevention of early-phase EBV-induced B-cell proliferation requires CD4+ effector T cells.
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Singh, K. K. „Expression of PD-L1 in human placenta and retained product of conception of early pregnancy loss“. American Journal of Clinical Pathology 160, Supplement_1 (01.11.2023): S80. http://dx.doi.org/10.1093/ajcp/aqad150.178.
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Abstract Introduction/Objective Immune surveillance evasion and impeding rejection by the maternal immune response system are elemental in sustaining foetal development. The exact mechanism behind this paradoxical immune response remains unclear. Since the trophoblast directly interacts with the maternal immune-environment, these cells must have some contribution to local immunosuppression. The programmed death-1 receptor and its ligands (PD- 1/PDL1)illustrates a novel regulatory-costulatory pathway that plays a major role in establishing peripheral tolerance. It was recently proved that PDL1 is expressed at the feto-maternal interface is necessary for maintaining feto-maternal tolerance. We undertook this study to determine the expression-pattern of PD-L1 in formalin-fixed paraffin embedded tissues of human placentas in third trimester and retained product in early spontaneous abortions. Methods/Case Report Clinical history were recorded. The H&E sections of 40 placenta & 20 RPOC cases were examined. After evaluation appropriate sections were selected for IHC examination using anti-PD-L1 antibodies of Lab-vision and Biogenic Results (if a Case Study enter NA) Main focus of study was to see expression of PD-L1 at feto-maternal interface. 30 out of 40 third-trimester placenta expressed PD-L1 immunohistochemistry (13, 11 and 6 cases showed intense, fair and weak positivity respectively on outer surface of syncytiotrophoblast). 2 out of 20 early pregnancy loss cases in 11 & 9wk gestation expressed PD-L1 positivity. Conclusion Fetal cells in direct contact with maternal blood villous syncytiotrophoblast are major source of PD-L1 at the maternal-fetal interface and may utilize these immuno-suppressive mechanisms to ensure tolerance of conceptus. Failure to adapt this mechanism can lead to pregnancy loss.
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Gao, Zetian, Qiubo Zhang, Xie Zhang und Yufei Song. „Advance of T regulatory cells in tumor microenvironment remodeling and immunotherapy in pancreatic cancer“. European Journal of Inflammation 20 (Januar 2022): 1721727X2210929. http://dx.doi.org/10.1177/1721727x221092900.
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Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, deadly, and is rarely diagnosed early. Regulatory T cells (Treg) are a multifunctional class of immunosuppressive T cells that help maintain immunologic homeostasis and participate in autoimmune diseases, transplants, and tumors. This cell type mediates immune homeostasis, tolerance, and surveillance and is associated with poor outcomes in PDAC. Tregs remodel the tumor immune microenvironment, mediate tumor immune escape, and promote tumor invasion and metastasis. A promising area of research involves regulating Tregs to reduce their infiltration into tumor tissues. However, the complexity of the immune microenvironment has limited the efficacy of immunotherapy in PDAC. Treg modulation combined with other treatments is emerging. This review summarizes the mechanisms of Tregs activity in tumor immune microenvironments in PDAC and the latest developments in immunotherapy and clinical trials.
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Christakou, Athanasia E., Mathias Ohlin, Björn Önfelt und Martin Wiklund. „Ultrasonic three-dimensional on-chip cell culture for dynamic studies of tumor immune surveillance by natural killer cells“. Lab on a Chip 15, Nr. 15 (2015): 3222–31. http://dx.doi.org/10.1039/c5lc00436e.
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We demonstrate 3D ultrasound cell culture for the formation of solid liver tumors in a multi-well microplate, and we use this method to simulate the early stages of tumor development under immune natural killer cell attack.
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Mestrallet, Guillaume. „Abstract 6652: Overcoming immune resistance in DNA mismatch repair deficient tumors“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 6652. http://dx.doi.org/10.1158/1538-7445.am2023-6652.
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Abstract Patients with Lynch Syndrome, an inherited mismatch repair deficiency, have an increased risk for developing microsatellite unstable (MSI-H) cancers. Our team recently identified shared immunogenic frameshift peptides in patient tumors that can be targets of T cell surveillance and preventative MSI-H cancer vaccines. We hypothesize that in Lynch Syndrome some premalignant lesions are capable of evading immune surveillance from cytotoxic T lymphocytes due to immune checkpoint expression and immunosuppression from tumor, myeloid and stromal cell populations. Immune checkpoint blockade (ICB) showed promising results in the treatment of MSI-H tumors and are being evaluated in the adjuvant setting of patients with Lynch syndrome post surgical resection. However, a significant percentage of advanced MSI-H tumors resist ICB suggesting evolving mechanisms of immune resistance. We will use a MSI-H in vivo mouse model and additionally develop 3D spheroids cocultured with immune cells to characterize the underlying immune resistance mechanisms. The MSI-H mouse model will first be applied to identify shared frameshifts in MSI-H tumors by WES to develop vaccination approaches preventing tumor growth. Then, we will quantify MSI-H tumor growth and immune infiltration in the MSI-H mouse model, with or without ICB. We will analyze the presence of immunosuppressive pathways and myeloid subsets in high growth resisting tumors by immunohistochemistry, scRNAseq, spatial transcriptomics and flow cytometry. In addition, we will perform short-term in vitro spheroid-splenic cell co-cultures to better characterize the early immune resistance mechanisms. We will also perform these spheroid-immune cell co-cultures using the immune cells taken from mice after vaccination or ICB to identify the early myeloid immune resistance mechanisms. Overall, the identification of shared immune frameshifts in MSI-H tumors will allow developing peptide vaccination approaches to prevent tumor growth. Further, the identification of myeloid resistance pathways will guide therapeutic strategies against tumor resisting to ICB and/or vaccination. Citation Format: Guillaume Mestrallet. Overcoming immune resistance in DNA mismatch repair deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6652.
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Cedro-Tanda, Alberto, Laura Gómez-Romero, Guillermo de Anda-Jauregui, Dora Garnica-López, Yair Alfaro-Mora, Sonia Sánchez-Xochipa, Eulices F. García-García et al. „Early Genomic, Epidemiological, and Clinical Description of the SARS-CoV-2 Omicron Variant in Mexico City“. Viruses 14, Nr. 3 (06.03.2022): 545. http://dx.doi.org/10.3390/v14030545.
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Omicron is the most mutated SARS-CoV-2 variant—a factor that can affect transmissibility, disease severity, and immune evasiveness. Its genomic surveillance is important in cities with millions of inhabitants and an economic center, such as Mexico City. Results. From 16 November to 31 December 2021, we observed an increase of 88% in Omicron prevalence in Mexico City. We explored the R346K substitution, prevalent in 42% of Omicron variants, known to be associated with immune escape by monoclonal antibodies. In a phylogenetic analysis, we found several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. A haplotype analysis revealed that there was no association between haplotype and vaccination status. Among the 66% of patients who have been vaccinated, no reported comorbidities were associated with Omicron; the presence of odynophagia and the absence of dysgeusia were significant predictor symptoms for Omicron, and the RT-qPCR Ct values were lower for Omicron. Conclusions. Genomic surveillance is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, and can inform public health decisions and detect the spread of any mutation that may affect therapeutic efficacy.
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Radom-Aizik, Shlomit. „Immune Response to Exercise During Growth“. Pediatric Exercise Science 29, Nr. 1 (Februar 2017): 49–52. http://dx.doi.org/10.1123/pes.2017-0003.
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Two papers were selected for this commentary. The first paper (Citation 1) suggests that a 10-week, moderate-intensity exercise program performed early after allogeneic hematopoietic stem cell transplantation is feasible in this fragile population, and might improve cell cytotoxicity by redistributing subpopulations of NK cells. This study adds to the growing evidence that enhancing immune cell surveillance (e.g., NK cells) in response to exercise could benefit cancer patients. The second paper (Citation 2) studied neutrophil-related mediators of oxidative stress and inflammatory cytokines in response to exercise in children compared with adults. The authors found age/maturation-related differences in these responses. The paper provides a valuable introduction to the current knowledge of maturational changes in immune mediators’ response to exercise. Data about leukocyte function in response to exercise in healthy children and in children with clinical conditions is scant. The need for prospective large scale pediatric clinical exercise studies is clear. Molecular approaches to understand the mechanisms through which physical activity can improve health will help to shape guidelines that optimize the mode, frequency, intensity, and duration of the training intervention.
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Su, Alan, Rodrigo Pedraza und Hagen Kennecke. „Developments in Checkpoint Inhibitor Therapy for the Management of Deficient Mismatch Repair (dMMR) Rectal Cancer“. Current Oncology 30, Nr. 4 (26.03.2023): 3672–83. http://dx.doi.org/10.3390/curroncol30040279.
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Deficient mismatch repair (dMMR)/microsatellite instability-high (MSIH) colorectal cancer is resistant to conventional chemotherapy but responds to immune checkpoint inhibition (ICI). We review the standard of care in locally advanced dMMR rectal cancer with a focus on ICI. We also present a case report to highlight the treatment complexities and unique challenges of this novel treatment approach. ICI can lead to immune related adverse events (irAEs), resulting in early treatment discontinuation as well as new challenges to surveillance and surgical management. Overall, neoadjuvant ICI can lead to robust treatment responses, but its impact on durable response and organ preservation requires further study.
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Venkatesh, Vishnu, Christine Yen, Ray Zhang, Anjali Rao, Alvin Chandra, Vlad Zaha, Srilakshmi Vallabhaneni und Kathleen W. Zhang. „Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with early-stage, triple-negative breast cancer.“ Journal of Clinical Oncology 41, Nr. 16_suppl (01.06.2023): 2607. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2607.
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2607 Background: Both pembrolizumab and anthracyclines (AC) can cause adverse cardiovascular events; combination therapy is approved for high-risk, early-stage, triple-negative breast cancer (TNBC) and may further increase real-world cardiovascular risk. Cardiac surveillance with serial troponin measurements has been advocated in this population, though evidence supporting this approach is lacking. Methods: High-sensitivity troponin I (hs-TnI) was prospectively measured at baseline and with each treatment cycle in cancer patients receiving immune checkpoint inhibitors (ICI) at a single center as part of an institutional surveillance protocol for ICI-related adverse events from 2020-2022. Acute cardiac injury was defined as ≥1 abnormal hs-TnI value (>17ng/dL in women and >35ng/dL in men) with normal baseline hs-TnI, or at least 20% increase in hs-TnI from abnormal baseline. The incidence of acute cardiac injury and all-cause mortality were compared between patients receiving ICI in combination with AC versus ICI without AC. Results: Among 215 patients treated with ICI with baseline and ≥1 follow-up hs-TnI value, 28 patients (13%) received ICI with AC, all of whom were women with early-stage TNBC receiving pembrolizumab and AC-containing chemotherapy. 187 patients (87%) received ICI without AC for other oncological indications. Patients receiving ICI with AC were younger and more likely to be female than patients receiving ICI without AC (p<0.001) with lower rates of smoking, hypertension, and diabetes (p<0.04). Acute cardiac injury was observed in 33 patients, 21% of those receiving ICI with AC (N=6) and 14% of those receiving ICI without AC (N=27; p=0.34). Among these 33 patients, 2 patients were treated for ICI-associated myocarditis (1 receiving ICI with AC, 1 receiving ICI without AC); 67% of those receiving ICI with AC (N=4) were continued on ICI while only 30% of those receiving ICI without AC (N=8) were continued on ICI (p=0.16). The rate of all-cause mortality was significantly lower in patients receiving ICI with AC (0%) as compared to patients receiving ICI without AC (40%, p<0.001). Conclusions: Among women with early stage TNBC receiving pembrolizumab with AC, the rate of acute cardiac injury by surveillance troponin measurements was numerically but not statistically higher than for patients receiving ICI without AC for other oncological indications, though the rate of all-cause mortality was significantly lower. These findings suggest that surveillance troponin monitoring may have less clinical utility among women with early-stage TNBC receiving ICI-based combination therapy as compared to other patient populations receiving ICI. Further study is needed to understand the mechanistic and prognostic significance of acute cardiac injury in patients with TNBC receiving ICI-based combination chemotherapy.
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Xu, Wenxi, Laura M. Snell, Mengdi Guo, Giselle Boukhaled, Bethany L. Macleod, Ming Li, Michael V. Tullius et al. „Uncovering the underlying immune perturbations that determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection“. Journal of Immunology 206, Nr. 1_Supplement (01.05.2021): 62.08. http://dx.doi.org/10.4049/jimmunol.206.supp.62.08.
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Abstract Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection, yet how they alter the pulmonary microenvironment to foster coinfection and worsen disease severity is unclear. We developed a coinfection model in mice with chronic lymphocytic choriomeningitis virus and Mtb coinfection that recapitulated the central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination and heightened mortality. These long-term disease consequences were not due to chronic virus-induced immunosuppression or exhaustion, but instead were determined by early alterations in immune surveillance of Mtb coinfection. Mechanistically, increased chronic virus induced TNFα production initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lung-draining lymph nodes (LNs) and allowing bacterial sanctuary. The inhibited antigen arrival to LNs delayed CD4 T cell priming, allowing Mtb to replicate to higher set-points before T cell mediated control could be initiated. Once primed, Mtb-specific CD4 T cell differentiation skewed away from the Th1 responses associated with Mtb control, and instead toward Th17 differentiation. The elevated IL17 increased pulmonary neutrophil influx that decreased the long-term survival of coinfected mice. Therapeutically correcting the timing of CD4 T cell priming re-established CD4 Th1 over Th17 dominance, diminished pulmonary neutrophilia, and enabled enhanced Mtb control in the presence of chronic viral coinfection. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function and foster long-term coinfection.
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McWilliam, Andrew S., Sylvia Napoli, Amanda M. Marsh, Francis L. Pemper, Delia J. Nelson, Carolyn L. Pimm, Philip A. Stumbles, Timothy N. C. Wells und Patrick G. Holt. „Dendritic Cells Are Recruited into the Airway Epithelium during the Inflammatory Response to a Broad Spectrum of Stimuli“. Journal of Experimental Medicine 184, Nr. 6 (01.12.1996): 2429–32. http://dx.doi.org/10.1084/jem.184.6.2429.
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A key rate-limiting step in the adaptive immune response at peripheral challenge sites is the transmission of antigen signals to T cells in regional lymph nodes. Recent evidence suggests that specialized dendritic cells (DC) fulfill this surveillance function in the resting state, but their relatively slow turnover in most peripheral tissues brings into question their effectiveness in signaling the arrival of highly pathogenic sources of antigen which require immediate mobilization of the full range of host defenses for maintenance of homeostasis. However, the present report demonstrates that recruitment of a wave of DC into the respiratory tract mucosa is a universal feature of the acute cellular response to local challenge with bacterial, viral, and soluble protein antigens. Consistent with this finding, we also demonstrate that freshly isolated respiratory mucosal DC respond in vitro to a variety of CC chemokines as well as complementary cleavage products and N-formyl-methionyl-leucine-phenylalanine. This suggests that rapid amplification of specific antigen surveillance at peripheral challenge sites is an integral feature of the innate immune response at mucosal surfaces, and serves as an “early warning system” to alert the adaptive immune system to incoming pathogens.
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Van Neste, Leander, Kirk J. Wojno, Ricardo Henao, Shrikant Mane, Howard Korman, Jason Hafron, Kenneth Kernen et al. „Evaluation of an RNAseq-Based Immunogenomic Liquid Biopsy Approach in Early-Stage Prostate Cancer“. Cells 10, Nr. 10 (28.09.2021): 2567. http://dx.doi.org/10.3390/cells10102567.
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The primary objective of this study is to detect biomarkers and develop models that enable the identification of clinically significant prostate cancer and to understand the biologic implications of the genes involved. Peripheral blood samples (1018 patients) were split chronologically into independent training (n = 713) and validation (n = 305) sets. Whole transcriptome RNA sequencing was performed on isolated phagocytic CD14+ and non-phagocytic CD2+ cells and their gene expression levels were used to develop predictive models that correlate to adverse pathologic features. The immune-transcriptomic model with the highest performance for predicting adverse pathology, based on a subtraction of the log-transformed expression signals of the two cell types, displayed an area under the curve (AUC) of the receiver operating characteristic of 0.70. The addition of biomarkers in combination with traditional clinical risk factors (age, serum prostate-specific antigen (PSA), PSA density, race, digital rectal examination (DRE), and family history) enhanced the AUC to 0.91 and 0.83 for the training and validation sets, respectively. The markers identified by this approach uncovered specific pathway associations relevant to (prostate) cancer biology. Increased phagocytic activity in conjunction with cancer-associated (mis-)regulation is also represented by these markers. Differential gene expression of circulating immune cells gives insight into the cellular immune response to early tumor development and immune surveillance.
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Cui, Min, Jiaolong Yuan, Chong Wang, Nan Zhang, Ke Wang, Kunlun Wang, Pingdong Hu, Xianwu Lin, Hong Yang und Zhenfang Fu. „Inhibition of T cell response by Japanese encephalitis virus: a mechanism of immune evasion (VIR5P.1019)“. Journal of Immunology 192, Nr. 1_Supplement (01.05.2014): 144.2. http://dx.doi.org/10.4049/jimmunol.192.supp.144.2.
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Abstract Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus, which can escape from the peripheral immune response resulting in serious neuroinflammation. However, the mechanism of JEV immune evasion still remains unclear. In our study, it was found that co-inhibitory molecules CD279 (PD-1) and CD272 (BTLA) were upregulated on T cells in JEV infected mouse. The increase of CD279 on CD8+ T cells was more obvious than on CD4+ T cells in the early stage of infection. The expression of CD274 (PD-1 ligand 1) was also upregulated on dendritic cells and macrophages accordingly. As a consequence, both CD4+ and CD8+ T cell population dramatically decreased in the early stage of infection. Moreover, the CD4+CD25+FoxP3+ regulatory T cells (Tregs) increased in the peripheral immune organs after JEV infection. Splenic Foxp3+ Treg cells kept expanding during the disease pregression; instead, in the blood, Tregs only increased in the early stage. IL-10, which indicating the immunosuppression, also dramatically increased in the same location. Collectively, our data suggest that there are four strategies involved in the JEV mediated immune evasion: upregulating the co-inhibitory molecules on T cells and APCs, inducing T cell apoptosis, expanding the Treg cells, and producing inhibitory cytokines. As a consequence, JEV escapes the immune surveillance and causes fatal CNS infection.
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Pankowska, Katarzyna Aneta, Grażyna Ewa Będkowska, Joanna Chociej-Stypułkowska, Małgorzata Rusak, Milena Dąbrowska und Joanna Osada. „Crosstalk of Immune Cells and Platelets in an Ovarian Cancer Microenvironment and Their Prognostic Significance“. International Journal of Molecular Sciences 24, Nr. 11 (25.05.2023): 9279. http://dx.doi.org/10.3390/ijms24119279.
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Ovarian cancer (OC) is one of the deadliest gynecological cancers, largely due to the fast development of metastasis and drug resistance. The immune system is a critical component of the OC tumor microenvironment (TME) and immune cells such as T cells, NK cells, and dendritic cells (DC) play a key role in anti-tumor immunity. However, OC tumor cells are well known for evading immune surveillance by modulating the immune response through various mechanisms. Recruiting immune-suppressive cells such as regulatory T cells (Treg cells), macrophages, or myeloid-derived suppressor cells (MDSC) inhibit the anti-tumor immune response and promote the development and progression of OC. Platelets are also involved in immune evasion by interaction with tumor cells or through the secretion of a variety of growth factors and cytokines to promote tumor growth and angiogenesis. In this review, we discuss the role and contribution of immune cells and platelets in TME. Furthermore, we discuss their potential prognostic significance to help in the early detection of OC and to predict disease outcome.
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Kim, Hyoji, Hoyun Choi und Suk Kyeong Lee. „Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by InhibitingBAD-Mediatedcaspase-3-Dependent Apoptosis“. Journal of Virology 90, Nr. 3 (18.11.2015): 1359–68. http://dx.doi.org/10.1128/jvi.02794-15.
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ABSTRACTEpstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and thein vivotriggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genesBRLF1andBZLF1as well asBcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels ofBRLF1andBZLF1were suppressed in cells followingBADknockdown and increased afterBADoverexpression. Progeny virus production was also downregulated by specific knockdown ofBAD. Our results demonstrated thatcaspase-3-dependent apoptosis is a prerequisite forBAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibitingBAD-mediatedcaspase-3-dependent apoptosis, which would trigger immediate early gene expression.IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressingBAD-inducedcaspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.
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Eaton, Valerie L., Damiano Fantini, Yanni Yu, Ming-Yi Chiang, Joshua Meeks, Joseph R. Podojil und Stephen D. Miller. „Early Suppression of Immune Regulatory Mechanisms Reduces Tumor Progression in a Murine Model of Urothelial Cancer“. Journal of Immunology 204, Nr. 1_Supplement (01.05.2020): 244.9. http://dx.doi.org/10.4049/jimmunol.204.supp.244.9.
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Abstract Urothelial cancer (UC) is the fifth most common cancer in the US. While cancer cells may be recognized initially by the immune system, this response is reduced as the tumor escapes immune surveillance over time. An understanding of the immune responses early in cancer progression could identify new therapies that can suppress tumor progression. To that end, we used a murine model of bladder cancer induced by the carcinogen BBN, which replicates the clinical presentation of UC in humans. RNAseq analysis of bladder tumors from mice exposed to BBN revealed an increase in immune regulatory signatures as early as 2 – 4 weeks post-initiation of exposure. These findings were confirmed by FACS analysis of spleen and bladders of mice at 0.5, 1, 2, 3 and 5 months post-initiation of exposure to BBN. The data show a bi-phasic pattern in the immune response, where there is an early increase in the number of Treg and Teff (CD4+ and CD8+) cells within the bladder at 0.5 – 1 months post-initiation of BBN exposure. The Treg and CD8+ T cells populations appear to decrease at 2 months and then increase at 3 and 5 months (corresponding to development of detectible tumor development). To determine if early suppression of Tregs affects tumor development, we depleted Tregs in wildtype C57BL/6 mice with anti-CD25 or diphtheria toxin treatment of Foxp3-DTR mice during the first month of BBN exposure. The data show that the absence of functional Tregs during the first month results in sustained Teff activity at 4 months. The increased Teff cells were found to induce a decrease in overall bladder weight, tumor development, and consequently contained fewer infiltrating immune cells. These findings suggest that early inhibition of Tregs allows for long-lived killing of tumor cells.
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Rao, Chinthalapally V., Chao Xu, Mudassir Farooqui, Yuting Zhang, Adam S. Asch und Hiroshi Y. Yamada. „Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma“. Cancers 13, Nr. 11 (25.05.2021): 2586. http://dx.doi.org/10.3390/cancers13112586.
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Chromosome Instability (CIN) in tumors affects carcinogenesis, drug resistance, and recurrence/prognosis. Thus, it has a high impact on outcomes in clinic. However, how CIN occurs in human tumors remains elusive. Although cells with CIN (i.e., pre/early cancer cells) are proposed to be removed by apoptosis and/or a surveillance mechanism, this surveillance mechanism is poorly understood. Here we employed a novel data-mining strategy (Gene Expression to Copy Number Alterations [CNA]; “GE-CNA”) to comprehensively identify 1578 genes that associate with CIN, indicated by genomic CNA as its surrogate marker, in human lung adenocarcinoma. We found that (a) amplification/insertion CNA is facilitated by over-expressions of DNA replication stressor and suppressed by a broad range of immune cells (T-, B-, NK-cells, leukocytes), and (b) deletion CNA is facilitated by over-expressions of mitotic regulator genes and suppressed predominantly by leukocytes guided by leukocyte extravasation signaling. Among the 39 CNA- and survival-associated genes, the purine metabolism (PPAT, PAICS), immune-regulating CD4-LCK-MEC2C and CCL14-CCR1 axes, and ALOX5 emerged as survival-critical pathways. These findings revealed a broad role of the immune system in suppressing CIN/CNA and cancer development in lung, and identified components representing potential targets for future chemotherapy, chemoprevention, and immunomodulation approaches for lung adenocarcinoma.
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Kline, Justin, James Godfrey und Stephen M. Ansell. „The immune landscape and response to immune checkpoint blockade therapy in lymphoma“. Blood 135, Nr. 8 (20.02.2020): 523–33. http://dx.doi.org/10.1182/blood.2019000847.
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Abstract The clinical development of effective cancer immunotherapies, along with advances in genomic analysis, has led to the identification of tumor environmental features that predict for sensitivity to immune checkpoint blockade therapy (CBT). Early-phase clinical trial results have demonstrated the remarkable effectiveness of CBT in specific lymphoma subtypes, including classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Conversely, CBT has been relatively disappointing in follicular lymphoma and diffuse large B-cell lymphoma. These clinical observations, coupled with important scientific discoveries, have uncovered salient features of the lymphoma microenvironment that correlate with immunotherapy response in patients. For example, classical Hodgkin lymphoma is characterized by an inflammatory environment, genetic alterations that facilitate escape from immune attack, and sensitivity to PD-1 blockade therapy. On the other hand, for lymphomas in which measures of immune surveillance are lacking, including follicular lymphoma and most diffuse large B-cell lymphomas, anti-PD-1 therapy has been less effective. An improved understanding of the immune landscapes of these lymphomas is needed to define subsets that might benefit from CBT. In this article, we describe the immune environments associated with major B-cell lymphomas with an emphasis on the immune escape pathways orchestrated by these diseases. We also discuss how oncogenic alterations in lymphoma cells may affect the cellular composition of the immune environment and ultimately, vulnerability to CBT. Finally, we highlight key areas for future investigation, including the need for the development of biomarkers that predict for sensitivity to CBT in lymphoma patients.
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Kosova, A. A., V. I. Chalapa, T. M. Itani und A. V. Semenov. „Epidemiological portrait of noroviral infection“. Ural Medical Journal 21, Nr. 3 (07.07.2022): 114–28. http://dx.doi.org/10.52420/2071-5943-2022-21-3-114-128.
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Introduction. Noroviruses are a common cause of acute gastroenteritis with significant public health burden, including outbreaks in health facilities, closed and semi-closed settings. This study aims to present a global overview and trends in noroviral epidemiology and highlights the important biological properties of norovirus. Materials and methods. The bibliographic databases (PubMed and Russian Science Citation Index) were searched based on the keyword “norovirus” (in English and Russian languages respectively) without restrictions and 338 papers were retrieved. Results and Discussion. Human noroviruses are highly genetically diverse and evolve rapidly, evading the host's immune response. In addition to being highly contagious, the lack of a robust cell culture system complicates vaccine development for noroviral infection prevention. This highlights the importance of surveillance and infection control measures, for efficient use of available healthcare resources for maximizing health benefits. Common preventive measures include providing the public with safe water and food (i.e. decontamination), improvement of hand hygiene, early detection, and isolation of infected individuals. Current surveillance techniques include sentinel surveillance, molecular surveillance, disease modeling, and prediction. Further investigations in the field of norovirus prevention and control and its economics are needed, since some studies demonstrate inconsistent results (i.e. effectiveness of hand sanitizers). Conclusion. Noroviral infections represent a significant public health burden and current surveillance techniques require further improvement in terms of sensitivity and accuracy. There is a need to push research in the field of prevention and control measures (safety of water and food supply, early isolation of infected patients, sufficient hand hygiene) and their effectiveness.
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Feng, Haokang, Jiale Feng, Xu Han, Ying Ying, Wenhui Lou, Liang Liu und Lei Zhang. „The Potential of Siglecs and Sialic Acids as Biomarkers and Therapeutic Targets in Tumor Immunotherapy“. Cancers 16, Nr. 2 (10.01.2024): 289. http://dx.doi.org/10.3390/cancers16020289.
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The dysregulation of sialic acid is closely associated with oncogenesis and tumor progression. Most tumor cells exhibit sialic acid upregulation. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors that recognize sialic acid and are expressed in various immune cells. The activity of Siglecs in the tumor microenvironment promotes immune escape, mirroring the mechanisms of the well-characterized PD-1/PD-L1 pathway in cancer. Cancer cells utilize sialic acid-linked glycans to evade immune surveillance. As Siglecs exhibit similar mechanisms as the established immune checkpoint inhibitors (ICIs), they are potential therapeutic targets for different forms of cancer, especially ICI-resistant malignancies. Additionally, the upregulation of sialic acid serves as a potential tumor biomarker. This review examines the feasibility of using sialic acid and Siglecs for early malignant tumor detection and discusses the potential of targeting Siglec–sialic acid interaction as a novel cancer therapeutic strategy.
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Sow, Mamadou Saliou, Josue Togo, Lacy M. Simons, Souleymane Taran Diallo, Mohamed Lamine Magassouba, Mamadou Bhoye Keita, Anou Moise Somboro et al. „Genomic characterization of SARS-CoV-2 in Guinea, West Africa“. PLOS ONE 19, Nr. 3 (06.03.2024): e0299082. http://dx.doi.org/10.1371/journal.pone.0299082.
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SARS-CoV-2 has claimed several million lives since its emergence in late 2019. The ongoing evolution of the virus has resulted in the periodic emergence of new viral variants with distinct fitness advantages, including enhanced transmission and immune escape. While several SARS-CoV-2 variants of concern trace their origins back to the African continent—including Beta, Eta, and Omicron–most countries in Africa remain under-sampled in global genomic surveillance efforts. In an effort to begin filling these knowledge gaps, we conducted retrospective viral genomic surveillance in Guinea from October 2020 to August 2021. We found that SARS-CoV-2 clades 20A, 20B, and 20C dominated throughout 2020 until the coincident emergence of the Alpha and Eta variants of concern in January 2021. The Alpha variant remained dominant throughout early 2021 until the arrival of the Delta variant in July. Surprisingly, despite the small sample size of our study, we also found the persistence of the early SARS-CoV-2 clade 19B as late as April 2021. Together, these data help fill in our understanding of the SARS-CoV-2 population dynamics in West Africa early in the COVID-19 pandemic.
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Xu, Yan, Yao Yao, Woojun Daniel Park, Sanika Derebail, Chandraditya Chakraborty, Shidai Mu, Rafael Alonso Fernández et al. „Enhancing the Immune Surveillance in Multiple Myeloma Via CDK4/6 Inhibition“. Blood 136, Supplement 1 (05.11.2020): 33–34. http://dx.doi.org/10.1182/blood-2020-143327.
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Deregulation of cyclin D genes is a uniform event in multiple myeloma (MM) and represent a striking addiction as observed in pan-cancer genome-wide CRISPR screening data. However, early stage Cyclin D and other cell cycle kinases inhibitors have shown a lack of single agent activity suggesting that targeting of cell cycle regulation is insufficient to produce a durable response in MM. Recent evidence recognizes the Cyclin D and CDK4 activities within the immune tumor microenvironment, supporting a previously unrecognized immunomodulatory functions of CDK4/6. This is particularly important in MM, a highly heterogeneous disease that resides in a complex ecosystem comprising of immune, endothelial, and stromal cells. We here evaluated the tumor intrinsic and extrinsic effects of CDK4/6 inhibition in MM with the goal to define rationally designed combination strategies to effectively impact MM growth. We have evaluated MM cell sensitivity to CDK4/6 inhibitors (both Palbociclib and Abemaciclib) in a panel of 32 MM cell lines and primary MM patients' samples. As expected, both inhibitors were mostly cytostatic with G0/G1 cell cycle arrest and significant impact on the pRB-E2F axis both in vitro as well as in vivo. In luminescence subcutaneous SCID models engrafted with H929 or MM1S MM cells expressing an E2F-driven luciferase reporter, treatment with low dose Palbociclib or Abemaciclib caused regression of bulky tumors, evidenced by a ~40% reduction in tumor volume at the 14-day end-point and a decreased E2F1 reporter activity. We next studied genome-wide transcriptional response to treatment using RNA-seq analysis in two MM cell lines using multiple doses and duration (24 and 72 hours) to evaluate the effect of short and long exposure to the drug. Gene set enrichment analysis (GSEA) of RNA-seq data confirmed significant downregulation of proliferation and E2F target genes at 24 hours post treatment. Interestingly, after longer exposure to both drugs we observed modulation of signatures for Ag presentation (including upregulation of HLA-A,B, and C; B2MG), innate immune response (ICAM-1 and 2; IL-8 and several CCLs) and interferon inducible genes IFN response (IRF1, IRF9, STAT1, STAT2, STAT4, OSA1, OSA2, MX1). To confirm genomic data and evaluate if CDK4/6i promotes the induction of the senescence-associated secretory phenotype (SASP) program in MM cells, we performed cytokine profile to assess the secretion of 174 soluble factors in the MM cell supernatant upon CDK4/6i. We confirmed a significant increase of chemokines involved in NK cell recruitment (CCL2, CCL4, CCL5), as well as cytokines that promote NK cell proliferation and activation. Moreover, we found that intercellular adhesion molecule-1 (ICAM-1) and the NKG2D ligands ULBP2 and MICA, required for activation of NK cell cytotoxicity and tumor cell targeting, were induced after CDK4/6i in MM cells. Although not secretory per se, these NK cell ligands are part of the transcriptional module linked to the SASP. Overall, these data suggest that, in addition to a more stable cell cycle arrest, CDK4/6i may promote MM cell immune surveillance through induction of the SASP program. To further confirm the immune effects, we tested freshly isolated NK cells from MM patients and healthy donors using in vitro MM-NK cell coculture assay and observed enhanced degranulation and cytokine production (intracellular IFN-γ and TNFα) by NK cells in response to MM cells. We finally investigated the potential of combining CDK4/6i with daratumumab in a standard 4-h ADCC assays using NK cells from MM patients as effector and MM cell lines as target. Daratumumab-mediated ADCC against MM cells was significantly augmented in the combination compared to single agent. In conclusion, we here report a novel anti-MM activity of CDK4/6i which is beyond the previously reported growth arrest. The observed ability to directly modulate the immune system along with decrease in the proliferative potential of MM cells may provide opportunities to develop unique combination approaches in MM. Disclosures Anderson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.. Fulciniti:NIH: Research Funding. Munshi:Takeda: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Legend: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company.
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Li, Xue, Kaifeng Pan, Michael Vieth, Markus Gerhard, Wenqing Li und Raquel Mejiías-Luque. „JAK-STAT1 Signaling Pathway Is an Early Response to Helicobacter pylori Infection and Contributes to Immune Escape and Gastric Carcinogenesis“. International Journal of Molecular Sciences 23, Nr. 8 (08.04.2022): 4147. http://dx.doi.org/10.3390/ijms23084147.
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Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04–5.30)). We observed that STAT1 was activated in human H. pylori-positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori, we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori-induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer.
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Addissouky, Tamer A., Ibrahim El Tantawy El Sayed, Majeed M. A. Ali, Yuliang Wang, Ayman El Baz, Ahmed A. Khalil und Naglaa Elarabany. „Can Vaccines Stop Cancer Before It Starts? Assessing the Promise of Prophylactic Immunization Against High-Risk Preneoplastic Lesions“. Journal of Cellular Immunology 5, Nr. 4 (29.11.2023): 127–40. http://dx.doi.org/10.33696/immunology.5.178.
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Background: Cancer remains a leading cause of mortality with modest declines, highlighting the need for more efficacious prevention strategies like early immunological intervention against premalignant disease. Main body of abstract: Oncogenic viruses demonstrate prophylactic vaccines can successfully reduce malignancy by blocking precipitating infections. However, most cancers lack viral etiology, requiring novel approaches targeting sporadic precancerous states to enable early immunoprevention. Preneoplastic tissues exhibit biological changes making them appealing targets for stimulating immune surveillance before additional mutations cause unconstrained proliferation. High-risk precancers also provide sources of dysregulated self-antigens. Yet challenges exist in lesion identification, overcoming tolerance, and avoiding inflammation potentially worsening progression. Multidisciplinary insights into precancer immunology, predictive biomarkers, antigen discovery, and combinatorial vaccination strategies are illuminating rational vaccine design. Despite obstacles, prophylactic immunization against early dysplastic changes holds disruptive potential if key steps advance this approach. Elucidating preneoplasia immunobiology and progression risk modeling will be critical to guide productive immune targeting while mitigating immunotherapy hazards. Thoughtful translation could eventually shift paradigms by priming immunosurveillance against peak vulnerability lesions. Short Conclusion: Advancements in precancer vaccines may profoundly expand prevention horizons. Cautious immune targeting of premalignant states could intercept progression toward widely disseminated malignancies. This warrants methodical efforts to unravel the promise of thwarting lethal cancers before they start.
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Rossi, Matilde, Nicole Cruz-Reyes, Melody L. Stallings Mann, Bryan M. McCauley, Tanya L. Hoskin, Robert A. Vierkant, Stacey J. Winham, Amy C. Degnim, Mark E. Sherman und Derek C. Radisky. „Abstract 4773: Interferon regulatory factor 8 (IRF8) as a biomarker for early detection and prevention of axillary lymph node-positive breast cancer“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 4773. http://dx.doi.org/10.1158/1538-7445.am2024-4773.
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Abstract Breast cancer (BC) remains a leading health concern worldwide and is often undetected until the cancer metastasizes. Early detection can limit the need for aggressive treatments and improve prognosis. We analyzed early immune and molecular markers in benign breast disease (BBD) biopsies prior to BC development to identify women at elevated risk of developing node-positive invasive BC, which might direct surveillance and prevention efforts aimed at reducing incidence of this disease. Utilizing the Mayo Clinic BBD cohort, we compared women who developed node-positive BC following their BBD biopsy (cases; n=42) with those who remained cancer-free (controls; n=37), matched on patient age and biopsy date. We used NanoString nCounter system to identify differentially expressed genes (DEGs) between cases and controls. We also developed a multiplex immunofluorescence (mIF) approach using Opal system by Akoya Biosciences for comprehensive marker detection in FFPE tissue, enabling correlation of cells expressing DEGs with innate and adaptive immune cells. Digitized images were segmented, and cell phenotyping, and spatial relationships were compared between cases and controls. Our findings revealed significantly increased expression levels of IRF8 (interferon regulatory factor 8, a factor involved in immune cell differentiation) in controls as compared to cases and found that increased IRF8 expression in cases is correlated with delayed cancer onset. Additionally, controls exhibited higher frequencies of CD4+, CD8+, CD68+, CD20+ and CD11c+ immune cells, and lower frequency of Ki67+ staining, with a notable increase of CD11c+/CD68+ cells, a marker for M1 type macrophages, indicating a pro-inflammatory, antitumorigenic immune microenvironment polarization. Furthermore, our mIF analyses offer new insights into spatial biomarker localization, enhancing prognostic accuracy. Our findings suggest that decreased numbers of immune cells in BBD biopsies may be associated with increased risk of developing axillary node-positive BC. This research underscores the importance of dissecting molecular and immune interactions in BBD for assessing the risk of this disease. Our results have the potential to improve individualized risk assessment, leading to more targeted surveillance and informed screening, potentially reducing BC incidence and mortality through early intervention. This study not only contributes to our understanding of BC pathogenesis but also opens avenues for developing novel preventive strategies. Citation Format: Matilde Rossi, Nicole Cruz-Reyes, Melody L. Stallings Mann, Bryan M. McCauley, Tanya L. Hoskin, Robert A. Vierkant, Stacey J. Winham, Amy C. Degnim, Mark E. Sherman, Derek C. Radisky. Interferon regulatory factor 8 (IRF8) as a biomarker for early detection and prevention of axillary lymph node-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4773.
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Shimozaki, Keitaro, Kenro Hirata, Sara Horie, Akihiko Chida, Kai Tsugaru, Yukie Hayashi, Kenta Kawasaki et al. „The Entire Intestinal Tract Surveillance Using Capsule Endoscopy after Immune Checkpoint Inhibitor Administration: A Prospective Observational Study“. Diagnostics 11, Nr. 3 (18.03.2021): 543. http://dx.doi.org/10.3390/diagnostics11030543.
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Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis. Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract. Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis (p = 0.0455). No adverse events related to CCE-2 were observed. Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.
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Gan, Chai, Bernard Kok Bang Lee, Shin Hin Lau, Thomas George Kallarakkal, Zuraiza Mohamad Zaini, Rosnah Binti Zain, Hans Prakash Sathasivam et al. „911 Immune profiling reveals enrichment of distinct immune signatures in high-risk oral potentially malignant disorders“. Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A957. http://dx.doi.org/10.1136/jitc-2021-sitc2021.911.
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BackgroundPatients with oral potentially malignant disorders (OPMD) having moderate or severe oral epithelial dysplasia (OED) have a greater risk of developing oral squamous cell carcinoma (OSCC) compared to mild OED with an odds ratio of 2.4.1 The involvement of specific immune cell types associated with malignant transformation have been reported, giving rise to clinical trials in immunoprevention. However, the immune landscape of OPMD remains understudied. In this study, we aimed to elucidate the immune landscape of high-risk OPMD by transcriptomic profiling for the identification of potential immunoprevention strategy.MethodsHistological evaluation was performed on hematoxylin and eosin (H&E)-stained tissues to investigate the differences of lymphocyte infiltration in benign lesions (n=16), high-risk OPMD consisted of moderate and severe OED (n=46) and early-stage OSCC (n=6). Formalin-fixed paraffin-embedded tissue sections of selected cases from each sample type were subjected to RNA sequencing. Weighted-gene-correlation network analysis (WGCNA) was used to identify key gene modules expressed in specific disease type.2 The immune landscape of high-risk OPMD was elucidated by the enrichment of immune signatures using single-sample gene set enrichment analysis.3–5 The response of high-risk OPMD to anti-PD1 treatment was predicted by the detection of T-cell-inflamed condition.6 Validation was performed by multiplex immunofluorescent (mIF) staining.ResultsOur H&E evaluation showed that lymphocyte infiltration into the epithelial was seen in 80% of high-risk OPMD and early-stage OSCC, compared to 9% of benign lesion. Gene modules identified from WGCNA analysis revealed that genes involved in immune-related pathways were overexpressed in high-risk OPMD and in early-stage OSCC when compared to benign lesion, but unchanged between high-risk OPMD and early-stage OSCC. We further demonstrated that immune signatures representing lymphocyte infiltration, MHC-I antigen presentation and cytotoxic immune responses were enriched in high-risk OPMD, indicating the presence of immune surveillance. High-risk OPMD can be grouped into the T-cell-inflamed and non-immune reactive subtypes. The T-cell-inflamed subtype is enriched with T cells, interferon signaling and PD-1/PD-L1 immune checkpoint proteins, suggesting that these lesions may be amenable to anti-PD1 treatment. Meanwhile, the non-immune reactive subtype demonstrated low enrichment in signatures for immune cell infiltration, indicating a need of intervention to induce lymphocyte infiltration. Using mIF staining, we observed an increase of CD45+ immune cell population expressing PD-L1 in high-risk OPMD.ConclusionsImmune surveillance is a prominent feature of high-risk OPMD. However, different subsets of high-risk OPMD exist, suggesting a need of different immunoprevention approaches to prevent disease progression which warrants further investigation.AcknowledgementsThis study was supported and funded by the Global Challenge Research Fund by the Medical Research Council, UK (MR/P024351/1) and Cancer Research Malaysia. We thank the Ong Heng Tiang & Ong Sek Pek Foundation for scholarship sponsorship.ReferencesIocca O, Sollecito TP, Alawi F, et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck 2020;42:539–55.Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559.Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.Chen YP, Wang YQ, Lv JW, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol 2019;30:68–75.Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018;48:812–30.Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017;127:2930–40.Ethics ApprovalThe use of clinical specimens in this study has been approved by the Medical Ethics Committee, Faculty of Dentistry, University of Malaya [DF OS1624/0073(L)], and The National Medical Research Register, Malaysia [NMRR-16-1764-32566 (IIR)].
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Engin, Ayse Basak, Riza Onder Gunaydin, Sacit Altug Kesikli, Dietmar Fuchs und Ali Sefik Hosal. „Serum neopterin concentrations and tryptophan degradation pattern in patients with late stage larynx carcinoma“. Pteridines 28, Nr. 2 (28.08.2017): 91–95. http://dx.doi.org/10.1515/pterid-2017-0004.
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AbstractAs the disease-free 5-year-survival of late stage laryngeal carcinoma patients is extremely low, indoleamine-2,3-dioxygenase-1 (IDO)-induced tryptophan degradation may represent an immune escape mechanism which plays an important role in cancer spreading in advanced stage laryngeal cancers. We examined whether the late stage laryngeal cancer enhances tumor immune evasion by the expression of systemic IDO activities and chronic cellular immune activation. Twenty-two of 42 male laryngeal cancer patients were classified as late stage cancer according to American Joint Committee on Cancer (AJCC) criteria. Their serum neopterin, tryptophan and kynurenine concentrations were compared with 30 cancer-free individuals. IDO activity was approved by correlation between serum neopterin and kynurenine/tryptophan. Late stage cancer patients preoperatively showed a significantly higher IDO activity compared to controls and early stage cancer cases. Six months after tumor removal, late stage cancer patients although having higher serum neopterin concentration compared to early stage patients or controls, they showed a significant decrease in IDO activity and tryptophan consumption. Increased systemic IDO activity may provoke the escape of tumor cells from the immune surveillance of the host. High IDO activity is due to the presence of tumor mass. Persistence of high serum neopterin levels despite tumor removal may indicate poor prognosis.
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Leo, Isabella, Mahesh Vidula, Giandomenico Bisaccia, Maria Cristina Procopio, Roberto Licordari, Maria Perotto, Giulia La Vecchia, Nikolaos Miaris, Paco E. Bravo und Chiara Bucciarelli-Ducci. „The Role of Advanced Cardiovascular Imaging Modalities in Cardio-Oncology: From Early Detection to Unravelling Mechanisms of Cardiotoxicity“. Journal of Clinical Medicine 12, Nr. 15 (27.07.2023): 4945. http://dx.doi.org/10.3390/jcm12154945.
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Advances in cancer therapies have led to a global improvement in patient survival rates. Nevertheless, the price to pay is a concomitant increase in cardiovascular (CV) morbidity and mortality in this population. Increased inflammation and disturbances of the immune system are shared by both cancer and CV diseases. Immunological effects of anti-cancer treatments occur with both conventional chemotherapy and, to a greater extent, with novel biological therapies such as immunotherapy. For these reasons, there is growing interest in the immune system and its potential role at the molecular level in determining cardiotoxicity. Early recognition of these detrimental effects could help in identifying patients at risk and improve their oncological management. Non-invasive imaging already plays a key role in evaluating baseline CV risk and in detecting even subclinical cardiac dysfunction during surveillance. The aim of this review is to highlight the role of advanced cardiovascular imaging techniques in the detection and management of cardiovascular complications related to cancer treatment.
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Santibanez, Juan F., und Suncica Bjelica. „Transforming Growth Factor-Beta1 and Myeloid-Derived Suppressor Cells Interplay in Cancer“. Open Cancer Immunology Journal 6, Nr. 1 (12.10.2017): 1–14. http://dx.doi.org/10.2174/1876401001706010001.
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Background: Transforming growth factor-beta1 (TGF-β1) is a pleiotropic cytokine with a double role in cancer through its capacity to inhibit early stages of tumors while enhancing tumor progression at late stages of tumor progression. Moreover, TGF-β1 is a potent immunosuppressive cytokine within the tumor microenvironment that allows cancer cells to escape from immune surveillance, which largely contributes to the tumor progression. Method: It has been established that the cancer progression is commonly associated with increased number of Myeloid-derived suppressor cells (MDSC) that are a hallmark of cancer and a key mechanism of immune evasion. Result: MDSC represent a population of heterogeneous myeloid cells comprised of macrophages, granulocytes and dendritic cells at immature stages of development. MDSC promote tumor progression by regulating immune responses as well as tumor angiogenesis and cancer metastasis. Conclusion: In this review, we present an overview of the main key functions of both TGF-β1 and MDSC in cancer and in the immune system. Furthermore, the mutual contribution between TGF-β1 and MDSC in the regulation of immune system and cancer development will be analyzed.
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Ní Chasaide, Caitlín, und Marina A. Lynch. „The role of the immune system in driving neuroinflammation“. Brain and Neuroscience Advances 4 (Januar 2020): 239821281990108. http://dx.doi.org/10.1177/2398212819901082.
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Neuroinflammation is now recognised as an important contributory factor in the progression of Alzheimer’s disease and probably also in the early stages of the disease. It is likely that this derives largely from aberrant activation of microglia, the resident mononuclear phagocytes of the brain. These cells are responsible for physiological immune surveillance and clearance of pathogens in the central nervous system, but evidence indicates that in Alzheimer’s disease, microglial function is compromised, and this contributes to the pathology. It is unclear what factors cause the inappropriate activation of the microglia in Alzheimer’s disease, but one contributor may be infiltrating peripheral immune cells and these include macrophages and T cells. It has been suggested that both cell types modulate the phenotype of microglia, highlighting the importance of crosstalk between the innate and adaptive immune system in Alzheimer’s disease. This review outlines our current knowledge of how cells of the peripheral immune system, specifically macrophages and T cells, may modulate microglial phenotype in the context of Alzheimer’s disease and considers the impact on their function, especially phagocytic capacity.
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Antea, Krsek, Krpina Kristina, Samarzija Miroslav, Detel Dijana, Baticic Lara und Sotosek Vlatka. „Immunotherapy in cancer: Where we are and what the future brings?“ Trends in Immunotherapy 7, Nr. 2 (12.10.2023): 2186. http://dx.doi.org/10.24294/ti.v7.i2.2186.
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Chemotherapy, radiotherapy, and surgery are recognized as the main treatment modalities for cancer. These therapeutic strategies may be effective in the early stages of the disease but are usually ineffective in advanced stages or when the cancer recurs. Recently, great efforts have been made to understand the complex interaction between the immune system and its surveillance of cancer and to find effective immunotherapies for all stages of cancer. Several types of immunotherapies, including adoptive immunotherapy, cancer vaccines, and immune checkpoint blockades, are receiving considerable attention. The clinical relevance of T lymphocytes and NK cells in combating carcinomas is beyond doubt, but their mechanism of tumor surveillance is far from being fully understood. In this review, much attention has been paid to the complex interplay between T lymphocytes, NK cells, and cancer cells and their role in immunotherapy. Moreover, in this review, we summarized the current data on cancer immunotherapies, especially cancer vaccines, T- and NK cell-based immunotherapies. In addition, we highlighted the role of biomarkers as important indicators of response to immunotherapy, as well as potential problems and solutions related to immunotherapy. Insights into the future of immunotherapy are also presented in this review.