Journal articles: 'IMMUNOESCAPE'

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Concha-Benavente, Fernando, Raghvendra M. Srivastava, Soldano Ferrone, and Robert L. Ferris. "EGFR-mediated tumor immunoescape." OncoImmunology 2, no. 12 (December 2013): e27215. http://dx.doi.org/10.4161/onci.27215.

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QUESNEL, BRUNO. "Tumor dormancy and immunoescape." APMIS 116, no. 7-8 (July 2008): 685–94. http://dx.doi.org/10.1111/j.1600-0463.2008.01163.x.

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Mazzolini, Guillermo. "Immunotherapy and immunoescape in colorectal cancer." World Journal of Gastroenterology 13, no. 44 (2007): 5822. http://dx.doi.org/10.3748/wjg.v13.i44.5822.

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Van hede, Dorien, Inge Langers, Philippe Delvenne, and Nathalie Jacobs. "Origin and immunoescape of uterine cervical cancer." La Presse Médicale 43, no. 12 (December 2014): e413-e421. http://dx.doi.org/10.1016/j.lpm.2014.09.005.

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Sauleda, Jaume, Francisco Javier Verdú, Sergio Scrimini, Ernest Sala, and Jaume Pons. "Immunoescape the link between emphysema and lung cancer?" Journal of Thoracic Disease 11, S3 (March 2019): S329—S330. http://dx.doi.org/10.21037/jtd.2018.12.133.

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Takasu, Chie, Shoko Yamashita, Yuji Morine, Kozo Yoshikawa, Takuya Tokunaga, Masaaki Nishi, Hideya Kashihara, Toshiaki Yoshimoto, and Mitsuo Shimada. "The role of the immunoescape in colorectal cancer liver metastasis." PLOS ONE 16, no. 11 (November 19, 2021): e0259940. http://dx.doi.org/10.1371/journal.pone.0259940.

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The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are less useful for monitoring the efficacy of therapy of CRC liver metastasis (CRLM). This study investigated the effects of immune molecules on the prognosis of CRLM. We enrolled 71 patients with CRLM who underwent curative resection for CRC. We used immunohistochemistry to analyze the expression of PD-1, PD-L1, indoleamine-pyrrole 2,3-dioxygenase (IDO), and CD163 (a marker of tumor-associated macrophages [TAMs]) in metastatic tumors. The immune molecules PD-1, PD-L1, IDO, and TAMs were expressed in 32.3%, 47.8%, 45.0%, and 47.9% of metastatic CRC samples, respectively. The 5-year overall survival rates associated with immune molecule-positive groups were significantly better than in the negative groups (PD-1: 87.7% vs 53.2%, p = 0.023; PD-L1: 82.4% vs 42.3%, p = 0.007; IDO: 80.7% vs 43.5%, p = 0.007; TAMs: 82.6% vs 48.0%, p = 0.005). Multivariate analysis revealed PD-1 expression (p = 0.032, hazard ratio: 0.19), IDO expression (p = 0.049, hazard ratio: 0.37), and tumor differentiation (p<0.001, hazard ratio: 0.02) as independent prognostic indicators. PD-1 and TAMs in metastases were associated with less aggressive features such as smaller tumors. Furthermore, TAMs positively and significantly correlated with PD-1 expression (p = 0.011), PD-L1 expression (p = 0.024), and tended to correlate with IDO expression (p = 0.078). PD-1, PD-L1, IDO, and TAMs in CRLM were associated with less aggressive features and better prognosis of patients with CRC, indicating adaptive antitumor immunity vs immune tolerance. These molecules may therefore serve as prognostic markers for CRLM.

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deCampos-Lima, Pedro-Otavio, Jelena Levitskaya, Teresa Frisan, and Maria G. Masucci. "Strategies of immunoescape in Epstein-Barr virus persistence and pathogenesis." Seminars in Virology 7, no. 1 (February 1996): 75–82. http://dx.doi.org/10.1006/smvy.1996.0009.

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Yaguchi, Tomonori, Hidetoshi Sumimoto, Chie Kudo-Saito, Nobuo Tsukamoto, Ryo Ueda, Tomoko Iwata-Kajihara, Hiroshi Nishio, Naoshi Kawamura, and Yutaka Kawakami. "The mechanisms of cancer immunoescape and development of overcoming strategies." International Journal of Hematology 93, no. 3 (March 2011): 294–300. http://dx.doi.org/10.1007/s12185-011-0799-6.

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Ghiringhelli, François, Mélanie Bruchard, Fanny Chalmin, and Cédric Rébé. "Production of Adenosine by Ectonucleotidases: A Key Factor in Tumor Immunoescape." Journal of Biomedicine and Biotechnology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/473712.

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It is now well known that tumor immunosurveillance contributes to the control of cancer growth. Many mechanisms can be used by cancer cells to avoid the antitumor immune response. One such mechanism relies on the capacity of cancer cells or more generally of the tumor microenvironment to generate adenosine, a major molecule involved in antitumor T cell response suppression. Adenosine is generated by the dephosphorylation of extracellular ATP released by dying tumor cells. The conversion of ATP into adenosine is mediated by ectonucleotidase molecules, namely, CD73 and CD39. These molecules are frequently expressed in the tumor bed by a wide range of cells including tumor cells, regulatory T cells, Th17 cells, myeloid cells, and stromal cells. Recent evidence suggests that targeting adenosine by inhibiting ectonucleotidases may restore the resident antitumor immune response or enhance the efficacy of antitumor therapies. This paper will underline the impact of adenosine and ectonucleotidases on the antitumor response.

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Wu, Lei, Yanquan Xu, Huakan Zhao, Yu Zhou, Yu Chen, Shuai Yang, Juan Lei, et al. "FcγRIIB potentiates differentiation of myeloid-derived suppressor cells to mediate tumor immunoescape." Theranostics 12, no. 2 (2022): 842–58. http://dx.doi.org/10.7150/thno.66575.

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Ogino, Takeshi, Shigetaka Moriai, Yoshiya Ishida, Hideyuki Ishii, Akihiro Katayama, Naoyuki Miyokawa, Yasuaki Harabuchi, and Soldano Ferrone. "Association of immunoescape mechanisms with Epstein-Barr virus infection in nasopharyngeal carcinoma." International Journal of Cancer 120, no. 11 (2007): 2401–10. http://dx.doi.org/10.1002/ijc.22334.

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Ferris, Robert L., Elizabeth M. Jaffee, and Soldano Ferrone. "Tumor Antigen–Targeted, Monoclonal Antibody–Based Immunotherapy: Clinical Response, Cellular Immunity, and Immunoescape." Journal of Clinical Oncology 28, no. 28 (October 1, 2010): 4390–99. http://dx.doi.org/10.1200/jco.2009.27.6360.

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PurposeTumor antigen (TA) –targeted monoclonal antibodies (mAb), rituximab, trastuzumab, and cetuximab, are clinically effective for some advanced malignancies, especially in conjunction with chemotherapy and/or radiotherapy. However, these results are only seen in a subset (20% to 30%) of patients. We discuss the immunologic mechanism(s) underlying these clinical findings and their potential role in the variability in patients' clinical response.MethodsWe reviewed the evidence indicating that the effects of TA-targeted mAb-based immunotherapy are mediated not only by inhibition of signaling pathways, but also by cell-mediated cytotoxicity triggered by the infused TA-targeted mAb. We analyzed the immunologic variables that can influence the outcome of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and in animal model systems. We also analyzed the correlation reported between these variables and the clinical response to mAb-based immunotherapy.ResultsOf the variables that influence ADCC mediated by TA-targeted mAb, only polymorphisms of Fcγ receptors (FcγR) expressed by patients' lymphocytes were correlated with clinical efficacy. However, this correlation is not absolute and is not observed in all malignancies. Thus other variables may be responsible for the antitumor effects seen in mAb-treated patients. We discuss the evidence that triggering of TA-specific cellular immunity by TA-targeted mAb, in conjunction with immune escape mechanisms used by tumor cells, may contribute to the differential clinical responses to mAb-based immunotherapy.ConclusionIdentification of the mechanism(s) underlying the clinical response of patients with cancer treated with TA-targeted mAb is crucial to optimizing their application in the clinic and to selecting the patients most likely to benefit from their use.

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Tirapu, Iñigo, Eduardo Huarte, Cristiana Guiducci, Ainhoa Arina, Mikel Zaratiegui, Oihana Murillo, Alvaro Gonzalez, et al. "Low Surface Expression of B7-1 (CD80) Is an Immunoescape Mechanism of Colon Carcinoma." Cancer Research 66, no. 4 (February 15, 2006): 2442–50. http://dx.doi.org/10.1158/0008-5472.can-05-1681.

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Romano, Veronica, Immacolata Belviso, Alessandro Venuta, Maria Rosaria Ruocco, Stefania Masone, Federica Aliotta, Giuseppe Fiume, Stefania Montagnani, Angelica Avagliano, and Alessandro Arcucci. "Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape." International Journal of Molecular Sciences 22, no. 10 (May 17, 2021): 5283. http://dx.doi.org/10.3390/ijms22105283.

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Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.

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Gabriele, Caterina, Licia E. Prestagiacomo, Giovanni Cuda, and Marco Gaspari. "Mass Spectrometry-Based Glycoproteomics and Prostate Cancer." International Journal of Molecular Sciences 22, no. 10 (May 14, 2021): 5222. http://dx.doi.org/10.3390/ijms22105222.

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Aberrant glycosylation has long been known to be associated with cancer, since it is involved in key mechanisms such as tumour onset, development and progression. This review will focus on protein glycosylation studies in cells, tissue, urine and serum in the context of prostate cancer. A dedicated section will cover the glycoforms of prostate specific antigen, the molecule that, despite some important limitations, is routinely tested for helping prostate cancer diagnosis. Our aim is to provide readers with an overview of mass spectrometry-based glycoproteomics of prostate cancer. From this perspective, the first part of this review will illustrate the main strategies for glycopeptide enrichment and mass spectrometric analysis. The molecular information obtained by glycoproteomic analysis performed by mass spectrometry has led to new insights into the mechanism linking aberrant glycosylation to cancer cell proliferation, migration and immunoescape.

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Iwami, Shingo, Hiroshi Haeno, and Franziska Michor. "A Race between Tumor Immunoescape and Genome Maintenance Selects for Optimum Levels of (epi)genetic Instability." PLoS Computational Biology 8, no. 2 (February 16, 2012): e1002370. http://dx.doi.org/10.1371/journal.pcbi.1002370.

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Ridolfi, Ruggero, Massimo Guidoboni, and Laura Ridolfi. "Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?" Journal of Nucleic Acids Investigation 1, no. 1 (May 19, 2010): 6. http://dx.doi.org/10.4081/jnai.2010.1724.

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The aryl hydrocarbon receptor (AhR), a member of the PAS protein family, is found in organisms as diverse as Drosophila melanogaster, nematodes, and mammals. While several reviews have reported that AhR, once activated by agonist ligands, causes long-term effects such as modification of cell growth through cell cycle control, there is also recent evidence of its decisive role in immunosuppression. The most widely studied AhR agonist is 2,3,7,8-tetrachlorodibenzo-p-dioxin, which binds AhR with the highest known affinity, leading to profound suppression of both humoral and cellular immune responses, with praecox thymus involution, consequent thymocyte loss, and induction of T-cell apoptosis. Dioxin-AhR binding causes a decline in the number of dendritic cells and enhances apoptosis following their inappropriate activation. Dioxin-mediated activation of AhR also has a direct influence on the expansion of regulatory T-cells CD4+CD25+ FoxP3+ (T-regs) and an adverse affect on CD8+ T-cell responses. Dioxin released from industrial and waste incinerators over the last few decades has caused widespread contamination of food, leading to its accumulation in fatty tissue in animals and humans. The elimination half-life of dioxin in humans (7-10 years) may favor the potentially continuous and long-lasting activation of AhR, leading to perpetual immune suppression and facilitating the onset, growth, and diffusion of tumors, especially in young people. In the cancer immunoediting hypothesis, which subdivides the relationship between tumor and immune system into three phases: elimination, equilibrium, and escape, it is thought that dioxin accumulation may cause an inevitable shift toward tumor escape.

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Gevorkian, Jonathan, Hein W. Verspaget, Daniel W. Hommes, Lin Chang, Charalabos Pothoulakis, and Stavroula Baritaki. "Mo1872 Corticotropin-Releasing Hormone Receptor 2 (CRHR2) Inhibits Colorectal Cancer Immunoescape Through Regulation of Fas/FasL Signaling." Gastroenterology 148, no. 4 (April 2015): S—732. http://dx.doi.org/10.1016/s0016-5085(15)32501-4.

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Cheng, An Ning, Li-Chun Cheng, Cheng-Liang Kuo, Yu Kang Lo, Han-Yu Chou, Chung-Hsing Chen, Yi-Hao Wang, Tsung-Hsien Chuang, Shih-Jung Cheng, and Alan Yueh-Luen Lee. "Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles." Journal for ImmunoTherapy of Cancer 8, no. 2 (December 2020): e001372. http://dx.doi.org/10.1136/jitc-2020-001372.

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BackgroundMitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).MethodsWe explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.ResultsWe found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.ConclusionsThe levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.

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Chimal-Ramírez, G. K., N. A. Espinoza-Sánchez, and E. M. Fuentes-Pananá. "Protumor Activities of the Immune Response: Insights in the Mechanisms of Immunological Shift, Oncotraining, and Oncopromotion." Journal of Oncology 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/835956.

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Experimental and clinical studies indicate that cells of the innate and adaptive immune system have both anti- and pro-tumor activities. This dual role of the immune system has led to a conceptual shift in the role of the immune system’s regulation of cancer, in which immune-tumor cell interactions are understood as a dynamic process that comprises at least five phases: immunosurveillance, immunoselection, immunoescape, oncotraining, and oncopromotion. The tumor microenvironment shifts immune cells to perform functions more in tune with the tumor needs (oncotraining); these functions are related to chronic inflammation and tissue remodeling activities. Among them are increased proliferation and survival, increased angiogenesis and vessel permeability, protease secretion, acquisition of migratory mesenchymal characteristics, and self-renewal properties that altogether promote tumor growth and metastasis (oncopromotion). Important populations in all these pro-tumor processes are M2 macrophages, N2 neutrophils, regulatory T cells, and myeloid derived suppressor cells; the main effectors molecules are CSF-1, IL-6, metalloproteases, VEGF, PGE-2, TGF-β, and IL-10. Cancer prognosis correlates with densities and concentrations of protumoral populations and molecules, providing ideal targets for the intelligent design of directed preventive or anticancer therapies.

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Liapis, Ioannis, and Stavroula Baritaki. "COVID-19 vs. Cancer Immunosurveillance: A Game of Thrones within an Inflamed Microenviroment." Cancers 14, no. 17 (September 5, 2022): 4330. http://dx.doi.org/10.3390/cancers14174330.

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The COVID-19 pandemic accounts for more than 500 million confirmed infections and over 6 million deaths worldwide in the last 2 years. SARS-CoV-2 causes a highly complex form of inflammation that affects the human organism both acutely and chronically. In the same line, cancer as an inflammation-induced and immune-editing disease appears to cross-react with immune system at different levels including early interactions during carcinogenesis and later cross-talks within the tumor microenvironment. With all that in mind, a reasonable question one might address is whether the SARS-CoV-2 infection and the derived “long lasting inflammatory status” that is frequently observed in patients, might affect the cancer immunosurveillance mechanisms and consequently their risk of developing cancer, as well as the tumor and immune cell behaviors within the inflamed microenvironment. On this context, this review intends to outline and discuss the existing knowledge on SARS-CoV-2-mediated immunomodulation under the prism of changes that might be able to interfere with cancer cell immunoescape and the overall tumor progression and response to conventional therapeutics. Our goal is to highlight a potential interplay between the COVID-19 immunopathology and cancer immune-microenvironment that may pave the way for thorough investigation in the future.

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Torretta, Enrica, Micaela Garziano, Mariacristina Poliseno, Daniele Capitanio, Mara Biasin, Teresa Antonia Santantonio, Mario Clerici, Sergio Lo Caputo, Daria Trabattoni, and Cecilia Gelfi. "Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature." International Journal of Molecular Sciences 22, no. 19 (September 22, 2021): 10198. http://dx.doi.org/10.3390/ijms221910198.

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The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient’s outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution.

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Youlin, Kuang, He Weiyang, Liang Simin, and Gou Xin. "Prostaglandin E2 Inhibits Prostate Cancer Progression by Countervailing Tumor Microenvironment-Induced Impairment of Dendritic Cell Migration through LXRα/CCR7 Pathway." Journal of Immunology Research 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/5808962.

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Migration and homing of dendritic cells (DCs) to lymphoid organs are quite crucial for T cell-induced immune response against tumor. However, tumor microenvironment can make some tumor cells escape immune response by impairing DC migration. Prostaglandin E2 (PGE2) plays important roles in initiating and terminating inflammatory responses. In this study, we investigated whether PGE2 could inhibit murine prostate cancer progression by countervailing tumor microenvironment-induced impairment of dendritic cell migration. We found that murine prostate cancer cell line RM-1-conditioned medium impaired chemotactic movement of marrow-derived DCs and splenic cDCs toward CC chemokine receptor-7 (CCR7) ligand CCL19 in vitro and migration to draining lymph gland in vivo. Meanwhile, it also induced LXRα activation and CCR7 inhibition on maturing DCs. However, the treatment of PGE2 rescued this impairment of DC migration with upregulation of CCR7 and inhibition of LXRα. Further, it was observed that PGE2 also increased MMP9 expression and activated Notch1 signaling on DCs. In RM-1-bearing mouse model, PGE2 treatment was identified to inhibit tumor growth and induce more tumor-infiltrating T cells and CD11c dendritic cells in tumor sites. Therefore, our findings may demonstrate a new perspective for therapeutic interventions on prostate cancer immunoescape.

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Kovar, Marek, Jakub Tomala, Helena Chmelova, Lubomir Kovar, Tomas Mrkvan, Radka Joskova, Zuzana Zakostelska, et al. "Overcoming Immunoescape Mechanisms of BCL1 Leukemia and Induction of CD8+ T-Cell–Mediated BCL1-Specific Resistance in Mice Cured by Targeted Polymer-Bound Doxorubicin." Cancer Research 68, no. 23 (December 1, 2008): 9875–83. http://dx.doi.org/10.1158/0008-5472.can-08-1979.

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Porcellato, Ilaria, Chiara Brachelente, Livia De Paolis, Laura Menchetti, Serenella Silvestri, Monica Sforna, Gaia Vichi, Selina Iussich, and Luca Mechelli. "FoxP3 and IDO in Canine Melanocytic Tumors." Veterinary Pathology 56, no. 2 (October 31, 2018): 189–99. http://dx.doi.org/10.1177/0300985818808530.

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Human melanoma is one of the deadliest forms of cancer, with poor prognosis and high resistance to chemotherapy and radiotherapy. The discovery of immunosuppressive mechanisms in the human melanoma microenvironment led to the use of new prognostic markers and to the development of immunotherapies targeting immune checkpoint molecules. Immunoescape mechanisms in canine melanoma have not yet been investigated, and no such immunotherapy has been tested. The aim of this study was to provide preliminary data on the expression of transcription factor forkhead box protein P3 (FoxP3) and indoleamine 2,3-dioxygenase (IDO) in primary canine melanocytic tumors and to investigate their prognostic role. Formalin-fixed, paraffin-embedded samples from 74 canine melanocytic tumors (26 oral melanomas, 23 cutaneous melanomas, and 25 cutaneous melanocytomas) were retrospectively evaluated by immunohistochemistry to explore the expression of FoxP3 and IDO. An increased risk of death due to melanoma was associated with a higher number of FoxP3+ cells per high-power field (FoxP3+/HPF), a higher percentage of CD3+ cells that were also FoxP3+ infiltrating and surrounding the tumor (%FoxP3), and a higher number of IDO+ cells/HPF (IDO+/HPF). A prognostic value for FoxP3 and IDO is suggested by our study, with optimal cutoffs of 14.7 FoxP3+ cells/HPF, 6.1 IDO+ cells/HPF, and 12.5% FoxP3+ cells. Both markers were also associated with tumor type. Multivariable analysis identified IDO+/HPF ( P < .001) as an independent prognostic marker. Even though stratification by diagnosis caused a loss of significance, results from the present study suggest a prognostic role for IDO and FoxP3, possibly related to the establishment of an immunosuppressive microenvironment.

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Fedders, Henning, Ameera Alsadeq, Britt-Sabina Petersen, Christian Kellner, Matthias Peipp, Thomas Valerius, Robert Haesler, et al. "Analyses of a Pair of Concordant Twins with Infant ALL and Discordant Clinical Outcome Reveals Immunoescape As a Mechanism of Disease Persistence in MLL-Rearranged Leukemia." Blood 124, no. 21 (December 6, 2014): 3791. http://dx.doi.org/10.1182/blood.v124.21.3791.3791.

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Abstract MLL-fusion is the most common genetic abnormality in acute lymphoblastic leukemia (ALL) of infancy and occurs in approximately 80% of the cases. Infant ALL represents a biologically distinctive entity with a highly immature pro-B immunophenotype associated with a particularly unfavorable prognosis due to a high proportion of early relapses. This may be due to the survival of dormant residual disease protected by the bone marrow niche. We have characterized a pair of monozygotic twin sisters diagnosed with ALL in early infancy. Tumor cells from both children carried the t(11;19) translocation (MLL-ENL fusion) and both patients were treated according to the ALL-BFM 2000 protocol. Despite good initial treatment responses in both twins, one sister developed very early relapse (twin A) and succumbed to the disease. The other went into continuous complete remission (twin B) and, as of today, is alive after 9 years. The clinical data of the 2 patients are presented in Table 1. Diagnostic bone marrow (BM) aspirates of both sisters were injected into the femoral bones of NOD SCID gamma (NSG) mice. Survival of xenografted mice bearing twin A was significantly longer due to a lower proliferative capacity of twin A as compared to twin B cells. In vivo Bromodeoxyuridine (BrdU) assays revealed that twin B cells were proliferating equally fast in BM and spleen, while in twin A cells, the BM markedly suppressed entry into S-phase. Flow cytometry from xenograft BM identified a large CD34+ population in twin A cells that was almost absent in twin B cells. Furthermore, BM of twin A xenografts showed a CD34+/CD38-/CD19- stem cell like population undetectable in twin B animals. Most interestingly, injection of minimal residual disease (MRD) negative remission bone marrow (PCR for Ig-gene rearrangements and the MLL-fusion gene) of both sisters into NSG mice resulted in a full-blown xenograft leukemia in animals bearing twin A but not twin B. Taken together, these data suggest that fatal relapse in twin A may be due to a quiescent stem cell like population kept in check by unknown mechanisms. Next, we performed gene expression analyses on xenografted leukemias from twin A (initial, leukemia amplified from remission BM, relapse) and from twin B (initial). STRING analysis of gene expression differences revealed that, amongst other findings related to cell cycle regulation and DNA-repair, twin A cells downregulated genes indicating a reduced interferon pathway activity (CXCL10, IFI30, TRAIL, STAT1, OAS1, MX1) and several genes connected to TYRO protein kinase binding protein (TYROBP) shown previously to regulate the activity of natural killer (NK) cells. This suggests that twin A cells may evade immunosurveillance as a mechanism of disease persistence. 51Chromium-release assays with IL-2 stimulated allogeneic NK cells from two healthy donors and the xenografted twin cells showed that twin A cells were significantly less sensitive to NK cell mediated lysis as compared to twin B cells. Whether the tumor cells also display differential susceptibility to antibody-dependent cell-mediated cytotoxicity is currently investigated. While the extensive genomic characterization of the twin leukemias is under way, we show evidence from xenograft experiments, gene expression profiles and functional in vitro experiments that dormant residual cells in MLL-rearranged ALL can evade immunosurveillance. These findings serve as a rationale to employ immunotherapeutic approaches in infant ALL patients in order to improve their dismal prognosis. Finally, we report the first monozygotic twin pair with MLL-rearranged ALL and discordant clinical outcomes. This provides a unique opportunity and a model to gain insight into the clonal composition of infant leukemia and the origins of leukemia relapse. Table 1: Patient characteristics of the MLL-ENL positive twin pair. WBC, white blood cells; BM, bone marrow; CNS, central nervous system; MRD, minimal residual disease. Parameter Twin A Twin B Age at diagnosis (days) 98 147 WBC (initial)/µl 334.000 103.000 Blasts (Peripheral Blood) % 97 91 Blasts (BM) % 98 97 CNS involvement Not determined Negative Immunophenotype Pro-B Pro-B Cytogenetics t(11;19) t(11;19) Prednisone-Response Poor Good Blasts (BM), day 15 % 32 1 MRD day 33 Negative Negative MRD day 78 Negative <10-4 * Event-free survival 227 days >9 years Time to relapse 227 days n/a Overall survival 390 days >9 years *low positive, not quantifiable Disclosures No relevant conflicts of interest to declare.

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Gorain, Bapi, Hira Choudhury, Gan Sook Yee, and Subrat Kumar Bhattamisra. "Adenosine Receptors as Novel Targets for the Treatment of Various Cancers." Current Pharmaceutical Design 25, no. 26 (October 9, 2019): 2828–41. http://dx.doi.org/10.2174/1381612825666190716102037.

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Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, even leading to metastases. The activity of adenosine exclusively depends upon the interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface. Research evidence supports that the activation of those receptors via specific agonist or antagonist can modulate the proliferation of tumour cells. The first category of AR, A1 is known to play an antitumour activity via tumour-associated microglial cells to prevent the development of glioblastomas. A2AAR are found in melanoma, lung, and breast cancer cells, where tumour proliferation is stimulated due to inhibition of the immune response via inhibition of natural killer cells cytotoxicity, T cell activity, and tumourspecific CD4+/CD8+ activity. Alternatively, A2BAR helps in the development of tumour upon activation via upregulation of angiogenin factor in the microvascular endothelial cells, inhibition of MAPK and ERK 1/2 phosphorylation activity. Lastly, A3AR is expressed in low levels in normal cells whereas the expression is upregulated in tumour cells, however, agonists to this receptor inhibit tumour proliferation through modulation of Wnt and NF-κB signaling pathways. Several researchers are in search for potential agents to modulate the overexpressed ARs to control cancer. Active components of A2AAR antagonists and A3AR agonists have already entered in Phase-I clinical research to prove their safety in human. This review focused on novel research targets towards the prevention of cancer progression through stimulation of the overexpressed ARs with the hope to protect lives and advance human health.

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Tsoukalas, Nikolaos, Ioannis Kostakis, Spiros Siakavellas, Maria Tolia, Aristoula Papakostidi, Andreas Karameris, Alexandros Tzovaras, et al. "The value of RCAS1 as a potential biomarker in non-small cell lung cancers." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21098-e21098. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21098.

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e21098 Background: RCAS1 (Receptor-binding Cancer Antigen expressed on SiSo cells) is a membrane protein that is expressed in different types of cancer. It halts the cell cycle and/or induces the apoptosis of the immune system cells within the tumour microenvironment. Hence, it is possible that this molecule is involved in the mechanism of the tumour cells’ escape from the immune system surveillance (immunoescape). Methods: Patients with primary non small cell lung cancer, initially eligible for surgical treatment, were included. The tissue samples (paraffin cubes) were processed using the Tissue Micro-arrays Method. Immunohistochemical study was done with specific monoclonal antibodies for RCAS1 and Ki-67. The image analysis was feasible due to a special program (image analysis software). In addition, a database was created that included the clinical and pathological characteristics of the patients. After the surgery patients received chemotherapy and/or radiotherapy according to the guidelines. Associations between variables were analyzed with non-parametric tests (Mann-Whitney and Kruskal-Wallis test) and the survival analysis with the Cox proportional hazards model. Two tailed p values ≤ 0.05 were considered to be statistically significant. Results: In total, 112 patients were examined (93 men and 19 women), mean age 63,6 years old. Almost 53% of the cases were adenocarcinoma, 33% squamous cell, 9% large cell, and 5% other types. Statistical significance was identified correlating RCAS1 over-expression to lower overall survival (p=0.032), to grade III (p=0.006) and in a positive correlation between RCAS1 and Ki-67 (p<0.001). Moreover, there is a trend of RCAS1 over-expression in advanced or metastatic stages and in tumours with lymphovascular invasion. In contrast, protein expression was not strongly associated to tumour size, to histological type, to patient age or to gender. Conclusions: The most important conclusions of this study are the negative correlation between RCAS1 and overall survival, the over-expression of RCAS1 in grade III tumors and the positive correlation between RCAS1 and Ki-67 which means that when Ki-67 increases RCAS1 is higher. Consequently, this molecule RCAS1 probably could be considered as a marker of the tumor’s aggressiveness.

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Ortego, Ignacio, Angel María Vizcay, Susana De La Cruz, Belén Pérez-Solans, Sandra Rubio, Javier Blanco, Miguel A. Idoate, et al. "Impact of dendritic cell vaccines added to neoadjuvant CT on pathological complete responses in early breast cancer patients according to PD-L1 expression." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 585. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.585.

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585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p < 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p < 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

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Guéry, Thomas, Christophe Roumier, Céline Berthon, Pascale Lepelley, Aline Renneville, Olivier Nibourel, Florent Dumezy, et al. "The B7-H3 Protein In Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 2620. http://dx.doi.org/10.1182/blood.v122.21.2620.2620.

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Abstract Introduction The B7 family of costimulatory molecules comprises several members, such as PD-L1 (B7-H1), that may participate in the immunoescape of tumor cells. For instance, the expression of PD-L1 in cancer cells can induce immunotolerance by deactivating T cells in several hematological malignancies, including acute myeloid leukemia (AML) and MDS. The B7-H3 (B7-homolog 3 or CD276) is a type I transmembrane protein and a member of the B7 family. B7-H3 is expressed in many tissues and in antigen-presenting cells. Its functions and counter receptor(s) remain unclear. The expression of the B7-H3 protein by the tumor microenvironment and tumor cells modifies the antitumor immune reaction, tumor growth, metastatic ability and drug resistance. B7-H3 is widely expressed in solid cancers and seems to be a prognostic marker in several tumor types. Clinical grade anti-B7-H3 antibodies are under development. The role of B7-H3 and its expression in AML has not yet been well investigated. We examined the expression of B7-H3 in the blast cells of a cohort of patients with AML to determine whether its expression affected the patients’ prognoses. Methods Our retrospective study included 111 patients (18 children and 93 adults) treated for AML between 2009 and 2011. We measured B7-H3 expression in bone marrow mononuclear cells using multiparameter flow cytometry (CD56, B7-H3, CD34, CD123, CD14, CD38 and CD45). We investigated the correlation of B7-H3 expression with biological, molecular and cytogenetic markers as well as the patient’s clinical characteristics. FLT3-ITD, NPM1 and CEBPA mutations were screened by the conventional Sanger methodology according to the ELN recommendations. Results B7-H3 expression was low and invariable in lymphocytes and high in monocytes. According to the MFI (Mean Fluorescence Intensity) ratio of blasts/lymphocytes, the B7-H3 expression level in blasts was widely variable (0.80 to 10.38). The threshold retained in our study was 3. Twenty seven percent (30/111) of AML samples were positive, and positive samples primarily included the M5 and M3 FAB subtypes (50% of B7-H3 positive patients). The expression of B7-H3 did not correlate with age (p=0.86), sex (p=0.79), leucocytosis (p=0.38) or NPM1 mutation status (p=0.08). The expression of B7-H3 was significantly higher in adverse karyotypes (p<0.05). The expression of B7-H3 was significantly lower in CEBPA mutations (p<0.05) and tended to be lower in Core Binding Factors AML (p = 0.054). In the 54 adults who were treated with intensive chemotherapy, B7-H3 did not affect the complete remission (CR) rate (81% in B7-H3 negative group, 89% in B7-H3, positive group, p=0.62) or the overall survival (p=0.73). Conclusion B7-H3 is highly expressed in a substantial fraction of AML cases, which suggests that it could serve as a possible therapeutic target. The significant differences in the B7-H3 expression between the different subgroups of AML according to FAB, cytogenetic or CEBPA mutational status should encourage further screening of B7-H3 in a larger prospective cohort of AML patients to obtain definitive conclusions about its prognostic value. Disclosures: Berthon: CELGENE: Research Funding. Preudhomme:CELGENE: Research Funding.

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Ramsay, Alan G., Andrew J. Clear, Alexander Davenport, Rewas Fatah, and John G. Gribben. "Chronic Lymphocytic Leukemia Cells Co-Opt CD200, CD270, CD274 and CD276 to Induce Impaired Actin Polarization At the T Cell Immune Synapse." Blood 118, no. 21 (November 18, 2011): 802. http://dx.doi.org/10.1182/blood.v118.21.802.802.

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Abstract Abstract 802 We have previously demonstrated that impaired formation of the T cell immunological synapse in response to autologous (auto) antigen-presenting cells (APCs) is a global immunosuppressive mechanism in chronic lymphocytic leukemia (CLL) (J Clin Invest. 2008;118(7):2427-2437). Polymerization of F-actin beneath the area of the T cell:APC contact site generates a structural support for signaling molecules to assemble and regulate appropriate CD4+ T cell activation and cytolytic CD8+ T cell (CTL) effector function. Importantly, direct contact interaction with tumor cells was shown to induce defective actin polarization at the synapse in previously healthy allogeneic (allo) peripheral blood (PB) T cells. Here we have extended our functional screening coculture assays and show that CD200, CD270 (TNF receptor, TNFR-superfamily 14, SF14), CD274 (programmed death ligand 1, PD-L1), and CD276 (B7-H3) are co-opted by primary CLL cells (n=25) to induce impaired actin polymerization at the CD3+ T cell synapse. Antibody neutralizaton of these CLL ligands significantly increased allo T cell synapse actin polymerization with APCs compared to isotype control treated cells (P<.01). Counteracting the combined activity of all four inhibitory proteins on CLL cells showed the largest increase in F-actin synapse polymerization. Importantly, we further demonstrate that direct contact coculture with CLL cells further augmented F-actin polymerization defects in auto PB patient T cells (isolated from low white blood cell count CLL patients), that was prevented by the prior blockade of these CLL inhibitory ligands (P<.01). Next we analyzed the in situ expression of inhibitory ligands and receptors by immunohistochemistry using a CLL lymphoid tissue microarray (TMA). Significantly higher expression of CD200+ CD270+ CD274+ CD276+ CD20+ CLL cells, and CD272+ (B and T lymphocyte attenuator, BTLA) CD279+ (PD-1) CD3+ T cells were detected compared to healthy counterpart cells from reactive control lymph node samples (P<.0001). Notably, higher expression of CD200+ CD274+ CLL cells correlated with poor disease outcome (P<.01). Flow cytometric analysis of peripheral blood patient cells showed that these inhibitory ligands were up-regulated on circulating CLL cells and also their receptors on auto T cells compared to age-matched healthy donor cells (P<.05). Next we investigated the impact of lenalidomide on CLL immunosuppressive signaling interactions with T cells. Both pretreatment of CLL cells with lenalidomide prior to primary coculture and direct addition of drug significantly increased (P <.01) subsequent allo T cell F-actin synapse polarization compared to control treated experiments. Flow cytometric analysis identified that lenalidomide downregulated the expression of these CLL inhibitory ligands and cognate receptors on allo T cells during intercellular contact interactions (P <.01), but not when age-matched healthy B cells were used. We next investigated the effect on cytolytic synapse function and demonstrated that allo CD8+ T cell killing function was significantly enhanced (P <.05) following combinational antibody blockade of CLL inhibitory ligands or lenalidomide treatment compared to control treated leukemic cells. Importantly, lenalidomide treatment blocked further augmented synapse impairment in auto T cells from CLL patients following coculture with CLL tumor cells. As members of the Rho family of GTPases, including RhoA, Rac1 and Cdc42 have been described as key regulators of actin polymerization, we measured their activated GTP-bound state in T cells following direct-contact interaction with CLL tumor cells. We demonstrate decreased active RhoA and Rac1 levels in TCR-stimulated allo T cells on coculture with CLL cells compared with primary coculture with healthy B cells (P <.05). In contrast, combinational antibody blockade of the CLL inhibitory ligands or lenalidomide treatment increased T cell Rho GTPase activity including Cdc42 (P <.05). In conclusion, our findings identify a new mechanism of cancer immunoescape in which CLL tumor cells co-opt multiple inhibitory B7-related molecules that can mediate global immunosuppressive actin defects in both auto and allo T cells. Disclosures: Gribben: Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria.

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Huang, Bo, and Xuetao Cao. "Metabolically targeting immunosuppression and immunoescape for future cancer immunotherapy: a narrative review." Holistic Integrative Oncology 1, no. 1 (November 4, 2022). http://dx.doi.org/10.1007/s44178-022-00018-5.

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AbstractCancer immunotherapy has emerged as the most important new approach to cancer treatments and moved rapidly to front-line therapy for certain types of cancers. However, both tumor microenvironments and tumor cells can mediate immunosuppression and immunoescape, thus dampening the efficacy of immunotherapy. Despite the complicacies, mechanistic illuminations of unknown immunosuppression and immunoescape are of paramount importance. This short review highlights the recent important findings in cancer immunology and immunotherapy, thus providing new insights into cancer immunosuppression, immunoescape and contributing to the design of innovative immunotherapeutics.

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Kresno, Siti Boedina. "Cancer Immunology: From Immunosurveillance to Immunoescape." Indonesian Journal of Cancer 2, no. 1 (March 31, 2008). http://dx.doi.org/10.33371/ijoc.v2i1.33.

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Sejak lama telah diketahui bahwa sistem imun dapat mengidentifikasi dan menyingkirkan sel tumor berdasarkan ekspresi antigen tumor atau molekul yang diinduksi oleh stres pada sel. Proses ini dikenal sebagai tumor immunosurveillance, pada proses mana sistem imun mengidentifikasi sel kanker dan sel prekanker kemudian menghancurkannya sebelum sel itu menjadi berbahaya. Berbagai sel efektor, seperti sel B, T, NK, NKT, IFN, perforin dan granzyme telah sejak lama diketahui secara jelas peranannya dalam immunosurveillance. Walaupun telah jelas bahwa ada immunosurveillance dan sel kanker dapat dikenal dan dihancurkan oleh sistem imun, mengapa kanker masih tetap dapat tumbuh dan berkembang pada orang yang imunokompeten? Berbagai penelitian telah membuktikan bahwa immunosurveillance hanyalah salah satu dimensi dari hubungan yang kompleks antara tumor dengan sistem imun. Juga telah banyak bukti bahwa sistem imun dapat merangsang munculnya tumor dengan imunogenesitas rendah yang mampu menghindar dari penghancuran oleh sistem imun. Penemuan ini mengakibatkan berkembangnya hipotesis baru yang dikenal sebagai hipotesis immunoediting.Tinjauan pustaka ini akan merangkum interaksi antara pejamu dengan sel-sel tumor yang berakibat eliminasi, ekilibrium clan escape, yang dikenal dengan istilah 3E dari proses immunoediting.

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Concha-Benavente, Fernando, and Robert L. Ferris. "Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy." Frontiers in Pharmacology 8 (May 30, 2017). http://dx.doi.org/10.3389/fphar.2017.00332.

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Wang, Yunfei, Kaikai Yi, Xing Liu, Yanli Tan, Weili Jin, Yansheng Li, Junhu Zhou, Hongjun Wang, and Chunsheng Kang. "HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas." Frontiers in Immunology 12 (November 23, 2021). http://dx.doi.org/10.3389/fimmu.2021.785463.

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BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTAIR is highly expressed and associated with metastasis in a variety of cancer types and promotes tumor metastasis at least in part through association with the PRC2 complex that induces redirection to hundreds of genes involved in tumor metastasis. Here, we report that HOTAIR is an activator lncRNA of the NF-κB pathway and demonstrate that its apparent upregulation promotes inflammatory signaling and immune escape in glioma cells.MethodsBioinformatics analysis was used to elucidate the relationship between HOTAIR and NF-κB pathway in HOTAIR knockdown glioma cells. At the cytological level, protein hybridization and immunofluorescence were used to detect the response of proteins in the NF-κB signaling pathway to HOTAIR regulation. ChIP and ChIRP experiments identified HOTAIR target genes. Animal experiments verified alterations in inflammation and immune escape following HOTAIR knockdown and activity inhibition.ResultsHOTAIR activated the expression of proteins involved in NF-κB, TNFα, MAPK and other inflammatory signaling pathways. In addition, HOTAIR induced various proteins containing protein kinase structural domains and promoted the enrichment of proteins and complexes of important inflammatory signaling pathways, such as the TNFα/NF-κB signaling protein complex, the IκB kinase complex, and the IKKA-IKKB complex. In addition, HOTAIR aberrantly activated biological processes involved in glioma immune responses, T-cell co-stimulation and transcription initiation by RNA polymerase II. HOTAIR facilitated the induction of IκBα phosphorylation by suppressing the expression of the NF-κB upstream protein UBXN1, promoting NF-κB phosphorylation and nuclear translocation. In vivo, reduction of HOTAIR decreased PD-L1 protein expression, indicating that cells are more likely to be targeted by immune T cells.ConclusionIn conclusion, our results provide convincing evidence that lncRNA HOTAIR drives aberrant gene transcription and immune escape from tumor cells through the NF-κB pathway.

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Porcellato, Ilaria, Chiara Brachelente, Katia Cappelli, Laura Menchetti, Serenella Silvestri, Monica Sforna, Samanta Mecocci, Selina Iussich, Leonardo Leonardi, and Luca Mechelli. "FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors." Veterinary Pathology, October 6, 2020, 030098582096013. http://dx.doi.org/10.1177/0300985820960131.

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Despite promising immunotherapy strategies in human melanoma, there are few studies on the immune environment of canine melanocytic tumors. In humans, the activation of immunosuppressive cell subpopulations, such as regulatory T cells (Tregs) that express forkhead box protein P3 (FoxP3), the engagement of immunosuppressive surface receptors like cytotoxic T lymphocyte antigen (CTLA-4), and the secretion of molecules inhibiting lymphocyte activation, such as indoleamine-pyrrole 2,3-dioxygenase (IDO), are recognized as immunoescape mechanisms that allow tumor growth and progression. The aim of our study was to investigate the expression of these immunosuppression markers in canine melanocytic tumors and to postulate their possible role in melanoma biology and progression. Fifty-five formalin-fixed, paraffin-embedded canine melanocytic tumors (25 oral melanomas; 20 cutaneous melanomas; 10 cutaneous melanocytomas) were selected to investigate the expression of FoxP3, CTLA-4, and IDO by immunohistochemistry and RT-qPCR (real-time quantitative polymerase chain reaction). All of the tested markers showed high gene and protein expression in oral melanomas and were differently expressed in cutaneous melanomas when compared to their benign counterpart. IDO expression was associated with an increased hazard of death both in univariable and multivariable analyses ( P < .05). FoxP3 protein expression >6.9 cells/HPF (high-power field) was an independent predictor of death ( P < .05). CTLA-4 gene and protein expressions were associated with a worse prognosis, but only in the univariable analysis ( P < .05). FoxP3, CTLA-4, and IDO likely play a role in canine melanoma immunoescape. Their expression, if supported by future studies, could represent a prognostic tool in canine melanoma and pave the way to future immunotherapeutic approaches in dogs.

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Kuo, Cheng-Liang, Ananth Ponneri Babuharisankar, Ying-Chen Lin, Hui-Wen Lien, Yu Kang Lo, Han-Yu Chou, Vidhya Tangeda, Li-Chun Cheng, An Ning Cheng, and Alan Yueh-Luen Lee. "Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend?" Journal of Biomedical Science 29, no. 1 (September 26, 2022). http://dx.doi.org/10.1186/s12929-022-00859-2.

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AbstractThe major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.

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Lei, Xinyuan, Hsinyu Lin, Jieqi Wang, Zhanpeng Ou, Yi Ruan, Ananthan Sadagopan, Weixiong Chen, et al. "Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression." Nature Communications 13, no. 1 (July 6, 2022). http://dx.doi.org/10.1038/s41467-022-31417-x.

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AbstractMitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.

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Pan, Jinghua, Yiting Qiao, Congcong Chen, Hongjing Zang, Xiaojing Zhang, Feng Qi, Cunjie Chang, et al. "USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1." Cell Death & Disease 12, no. 11 (November 2021). http://dx.doi.org/10.1038/s41419-021-04356-6.

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AbstractPD-L1(CD274) is a well-known immunosuppressive molecule, which confers immunoescape features to cancer cells and has become one of the major targets in cancer immunotherapies. Understanding the regulatory mechanisms that control PD-L1 protein expression is important for guiding immune checkpoint blockade therapy. Here, we showed that ubiquitin specific peptidase 5 (USP5) was a novel PD-L1 deubiquitinase in non-small cell lung cancer (NSCLC) cells. USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability. Meanwhile, USP5 protein levels were highly elevated and positively correlated to PD-L1 levels in NSCLC tissues, and were closely correlated with poor prognosis of these patients. In addition, knockdown of USP5 retarded tumor growth in the Lewis lung carcinoma mouse model. Thus, we identified that USP5 was a new regulator of PD-L1 and targeting USP5 is a promising strategy for cancer therapy.

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Braumüller, Heidi, Bernhard Mauerer, Christopher Berlin, Dorothea Plundrich, Patrick Marbach, Pierre Cauchy, Claudia Laessle, Esther Biesel, Philipp Anton Holzner, and Rebecca Kesselring. "Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment." Frontiers in Immunology 13 (June 30, 2022). http://dx.doi.org/10.3389/fimmu.2022.908449.

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More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC.

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Bogéa, Gabriela Muller Reche, Amandda Évelin Silva-Carvalho, Luma Dayane de Carvalho Filiú-Braga, Francisco de Assis Rocha Neves, and Felipe Saldanha-Araujo. "The Inflammatory Status of Soluble Microenvironment Influences the Capacity of Melanoma Cells to Control T-Cell Responses." Frontiers in Oncology 12 (March 28, 2022). http://dx.doi.org/10.3389/fonc.2022.858425.

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The development of immunotherapeutic approaches for the treatment of melanoma requires a better understanding of immunoescape mechanisms of tumor cells and how they interact with other tumor-resident cell types. Here, we evaluated how the conditioned media of resting (rCM) and immune-activated PBMCs (iCM) influence the ability of a metastatic melanoma cell line (MeWo) to control T-cells function. MeWo cells were expanded in RPMI, rCM, or iCM and the secretome generated after cell expansion was identified as MeSec (RPMI), niSec (non-inflammatory), or iSec (inflammatory secretome), respectively. Then, the immunomodulatory potential of such secretomes was tested in PHA-activated PBMCs. iCM induced higher levels of IFN-γ and IL-10 in treated melanoma cells compared to rCM, as well as higher IDO and PD-L1 expression. The iSec was able to inhibit T-cell activation and proliferation. Interestingly, PBMCs treated with iSec presented a reduced expression of the regulators of Th1 and Th2 responses T-BET and GATA-3, as well as low expression of IFN-γ, and co-stimulatory molecules TIM-3 and LAG-3. Importantly, our findings show that melanoma may benefit from an inflammatory microenvironment to enhance its ability to control the T-cell response. Interestingly, such an immunomodulatory effect involves the inhibition of the checkpoint molecules LAG-3 and TIM-3, which are currently investigated as important therapeutic targets for melanoma treatment. Further studies are needed to better understand how checkpoint molecules are modulated by paracrine and cell contact-dependent interaction between melanoma and immune cells. Such advances are fundamental for the development of new therapeutic approaches focused on melanoma immunotherapy.

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Alsadeq, A., H. Fedders, BS Petersen, C. Kellner, M. Peipp, M. Bulduk, T. Valerius, et al. "A Case of Concordant Twins with Infant ALL and Discordant Clinical Outcome – Part II: highlights on an immunoescape phenotype as a potential mechanism of disease persistence." Klinische Pädiatrie 227, no. 03 (July 27, 2015). http://dx.doi.org/10.1055/s-0035-1550250.

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Moyano, Ana, Oscar Blanch-Lombarte, Laura Tarancon-Diez, Nuria Pedreño-Lopez, Miguel Arenas, Tamara Alvaro, Concepción Casado, et al. "Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control." Retrovirology 19, no. 1 (March 26, 2022). http://dx.doi.org/10.1186/s12977-022-00591-7.

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Abstract Background Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs. Results In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC. Conclusions These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.

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