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      The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer

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          Abstract

          Pancreatic ductal adenocarcinoma ( PDA) is associated with an immunosuppressive tumor‐microenvironment ( TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 ( PD‐L1) and loss of human leukocyte antigen ( HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD‐L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLADR, PD‐L1, PD‐1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLADR, PD‐L1 or PD‐1 and the pattern of tumor infiltrating immune cells or the patients’ prognosis were assessed. PD‐L1 expression correlated with tumor infiltration by CD68 + and FoxP3 + cells. Low HLA class I expression was an only risk factor for poor survival. PD‐L1 negative and HLA class I high‐expressing PDA was significantly associated with higher numbers of infiltrating CD8 + T cells in the TME, and a better prognosis. Evaluation of both PD‐L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD‐1/ PD‐L1 immune checkpoint blockade therapies.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            In search of the ‘missing self’: MHC molecules and NK cell recognition

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              Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

              The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early "elimination phase" of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.
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                Author and article information

                Contributors
                okap@surg2.med.kyushu-u.ac.jp
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                10 June 2017
                July 2017
                : 6
                : 7 ( doiID: 10.1002/cam4.2017.6.issue-7 )
                : 1614-1626
                Affiliations
                [ 1 ] Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan
                [ 2 ] Department of General surgery Digestive Disease and Surgery institute Cleveland Clinic Cleveland USA
                [ 3 ] Department of Pathology and Microbiology Saga Medical School Faculty of Medicine Saga University Saga Japan
                [ 4 ] Department of Anatomic Pathology Pathological sciences Graduate School of Medical Sciences Kyushu University Fukuoka Japan
                Author notes
                [*] [* ] Correspondence

                Shinji Okano, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1, Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan. Tel: 81 92 642 5466; Fax: 81 92 642 5482; E‐mail: okap@ 123456surg2.med.kyushu-u.ac.jp

                Article
                CAM41087
                10.1002/cam4.1087
                5504334
                28602029
                615b843b-4e55-4dea-b617-4cdd50b9b7fe
                © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 December 2016
                : 02 April 2017
                : 04 April 2017
                Page count
                Figures: 5, Tables: 2, Pages: 13, Words: 7127
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                cam41087
                July 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

                Oncology & Radiotherapy
                biomarker,human leukocyte antigens class i,immunotherapy,pancreatic cancer,programmed cell death ligand 1

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