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      Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies

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          Abstract

          A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility.

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          Most cited references67

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          T Cell Dysfunction in Cancer.

          Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
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            Adaptive Immune Resistance: How Cancer Protects from Immune Attack.

            Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1-blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies.
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              PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers

              BACKGROUND. PD-L1 expression and tumor mutational burden (TMB) have emerged as important biomarkers of response to immune checkpoint inhibitor (ICI) therapy. These biomarkers have each succeeded and failed in predicting responders for different cancer types. We sought to describe the PD-L1 expression landscape across the spectrum of ICI-responsive human cancers, and to determine the relationship between PD-L1 expression, TMB, and response rates to ICIs. METHODS. We assessed 9887 clinical samples for PD-L1 expression and TMB. RESULTS. PD-L1 expression and TMB are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson’s correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer. CONCLUSION. Our results indicate that PD-L1 expression and TMB may each inform the use of ICIs, point to different mechanisms by which PD-L1 expression regulates ICI responsiveness, and identify new opportunities for therapeutic development. FUNDING. Funding was provided by Foundation Medicine Inc., the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, the Viragh Foundation, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), the Norman & Ruth Rales Foundation, and the Conquer Cancer Foundation. PD-L1 expression and tumor mutational burden, two widely utilized biomarkers for cancer immunotherapy, are not significantly correlated within most cancer subtypes.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                10 August 2019
                August 2019
                : 11
                : 8
                : 1150
                Affiliations
                [1 ]Genetics of Non-communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
                [2 ]Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran
                [3 ]Department of Clinical Biochemistry, Iranshahr University of Medical Sciences, Iranshahr 9916643535, Iran
                [4 ]Instititute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education in Katowice, 40-065 Katowice, Poland
                [5 ]Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
                [6 ]Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
                [7 ]Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
                Author notes
                Author information
                https://orcid.org/0000-0002-6074-7101
                https://orcid.org/0000-0001-5948-508X
                Article
                cancers-11-01150
                10.3390/cancers11081150
                6721817
                31405171
                baeed2ee-a4bf-45d2-a7f0-c546a1d8f793
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 June 2019
                : 07 August 2019
                Categories
                Article

                apoptosis,pd-1,pd-l1,polymorphism,cancer,meta-analysis
                apoptosis, pd-1, pd-l1, polymorphism, cancer, meta-analysis

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