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Check point inhibitors are a novel class of immunomodulators with ability to reverse the anergy of T-cells in the tumor microenvironment. Two main co-stimulatory inhibitory molecules have been targeted with these molecules: the CTLA-4/CD80- CD86 and the PD-1/PD-L1-PDL-2 axis. Ipilimumab (anti-CTLA-4) inhibits the binding of CTLA-4 to CD80 and CD86 and has been clinically approved for patients with metastatic melanoma. Many clinical trials with antibodies blocking the PD-1/PD-L1 pathways have shown impressive results in patients with metastatic melanoma, renal cell carcinoma, non-small lung cell carcinoma, head and neck cancer, and ovarian cancer. Due to their efficacy in only a subgroup of patients and their major cost, biomarkers allowing a better selection of patient are eagerly awaited. Our group and others showed that expression of checkpoint inhibitors on T-cells in the blood did not reflect their expression in the tumor microenvironment. Up until now no blood biomarker able to predict clinical response to checkpoint inhibitors have been identified. So current studies switched to the analysis of the phenotype of tumor and infiltrating immune cells as predictive biomarker to checkpoint inhibitors efficacy. Expression of PD-L1 in the tumor microenvironment may represent a biomarker to select patients, but its measure has to be standardized. Other emergent biomarkers include the qualitative analysis of the immune cells in the tumor microenvironment and the cross talk between tumor cells and stromal cells locally. [ABSTRACT FROM AUTHOR]

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: HP reports personal fees from MSD, Janssen, and Biomerieux. ET reports research grants from Servier and Vaxeal; reports honorarium fees from BMS and Merck-MSD; reports honorarium fees for participation on advisory boards from BMS and Astra-Zeneca. PLT reports honorarium fees for participation on advisory boards for Retrophin Inc not related to this work. JBA reports consultancy/expert testimony and honoraria from Novartis and Pfizer. BC reports receiving consulting fees and honoraria for lectures at symposia from Edwards Life Sciences, Orion Pharma, Amomed, and Nordic Pharma. MZ reports research grants from the French Ministry of Health, Quantum Genomics, and the European Horizon 2020 program; reports grant support and nonfinancial support from ReCor Medical and Idorsia; and reports personal fees from CVRx. JSH reports grants from Bioserenity, Sanofi, Servier and Novo Nordisk. J.S.H; reports speaker, advisory board or consultancy fees from Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Novartis, Novo Nordisk. SC reports personal fees from Novonordisk, Lilly, Kabi, Janssen-Cilag, Servier, outside the submitted work; reports other from MyGoodLife. FP reported receiving grants from Bristol-Myers and Squibb and HalioDx outside the submitted work; participation in Scientific Advisory Boards & Meetings for Bristol-Myers Squibb, Roche, Janssen, Merck, and Gilead. DMS received consulting fees or travels expenses from Boehringer Ingelheim, Léo Pharma, Aspen and Carmat. None of them are related to the work described here. M-ADD reported having received speaker fees from BMS, Gilead and Roche outside the submitted work. The remaining authors declared no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

T cells harboring multiple co-inhibitory molecules lose their anti-tumoral functionality. PD-1 is a clinically approved target in cancer therapy, but its expression alone does not mean dysfunctionality. The expression of Tim-3 on numerous cell types (T cell, Treg, dendritic cell, myeloid cells) favors tumor escape to immune cells. Within many tumors, PD-1/Tim-3 coexpressing CD8-T cells lose their ability to secrete cytokines (IFNγ, IL-2, TNFα) and their intratumoral infiltration correlates with a bad prognosis. Tim-3 recently appeared as a potential biomarker of anti-PD-1 resistance. Combined blockade of PD-1 and Tim-3 axis demonstrated potent clinical efficacy in preclinical models and reinforced the rationale of using an anti-Tim-3 to override tumor resistance., (© 2018 médecine/sciences – Inserm.)

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8 + T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8 + T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8 + T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1 + Tim-3 + subset of CD8 + T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3 + PD1 + CD8 + T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075-82. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Costimulatory molecules allow the full lymphocyte activation, whereas co-inhibitory molecules are negative counterparts that act as immune regulators, avoiding excessive response. In some context of chronic inflammation such as cancer, co-inhibitory immune checkpoint as CTLA-4, PD-1, Lag-3, Tim-3 can accumulate at the membrane of T cells leading to a state of anergy and therefore the loss of tumor growth control. Consequently, these immune checkpoints are considered as potential target in the treatment of cancer. Immunotherapy by anti-CTLA-4 and anti-PD-1/PD-L1 early demonstrated very good proof of efficacy in the setting of several cancers types, supporting the role of these molecules in tumor immune escape. The aim of this review is to summarize the pathophysiology of immune checkpoints and their therapeutic applications in cancer., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)