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      T Lymphocytes: A Promising Immunotherapeutic Target for Pancreatitis and Pancreatic Cancer?

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          Abstract

          Pancreatic disorders cause a broad spectrum of clinical diseases, mainly including acute and chronic pancreatitis and pancreatic cancer, and are associated with high global rates of morbidity and mortality. Unfortunately, the pathogenesis of pancreatic disease remains obscure, and there is a lack of specific treatments. T lymphocytes (T cells) play a vital role in the adaptive immune systems of multicellular organisms. During pancreatic disease development, local imbalances in T-cell subsets in inflammatory and tumor environments and the circulation have been observed. Furthermore, agents targeting T cells have been shown to reverse the natural course of pancreatic diseases. In this review, we have discussed the clinical relevance of T-cell alterations as a potential outcome predictor and the underlying mechanisms, as well as the present status of immunotherapy targeting T cells in pancreatitis and neoplasms. The breakthrough findings summarized in this review have important implications for innovative drug development and the prospective use of immunotherapy for pancreatitis and pancreatic cancer.

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          Most cited references144

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          Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.

          Cancer incidence and deaths in the United States were projected for the most common cancer types for the years 2020 and 2030 based on changing demographics and the average annual percentage changes in incidence and death rates. Breast, prostate, and lung cancers will remain the top cancer diagnoses throughout this time, but thyroid cancer will replace colorectal cancer as the fourth leading cancer diagnosis by 2030, and melanoma and uterine cancer will become the fifth and sixth most common cancers, respectively. Lung cancer is projected to remain the top cancer killer throughout this time period. However, pancreas and liver cancers are projected to surpass breast, prostate, and colorectal cancers to become the second and third leading causes of cancer-related death by 2030, respectively. Advances in screening, prevention, and treatment can change cancer incidence and/or death rates, but it will require a concerted effort by the research and healthcare communities now to effect a substantial change for the future. ©2014 American Association for Cancer Research.
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            Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

            Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
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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
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                24 March 2020
                2020
                : 10
                : 382
                Affiliations
                [1] 1Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University , Dalian, China
                [2] 2Institute (College) of Integrative Medicine, Dalian Medical University , Dalian, China
                [3] 3School of Chemical Engineering, Dalian University of Technology , Dalian, China
                [4] 4Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University , Dalian, China
                Author notes

                Edited by: Catherine Sautes-Fridman, INSERM U1138 Centre de Recherche des Cordeliers, France

                Reviewed by: Ying Ma, University of Texas MD Anderson Cancer Center, United States; Manel Juan, Hospital Clínic de Barcelona, Spain

                *Correspondence: Hong Xiang xianghong0806@ 123456163.com

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work and share first authorship

                Article
                10.3389/fonc.2020.00382
                7105736
                32266154
                012a4f47-b140-4841-9417-b73238172406
                Copyright © 2020 Zhou, Tao, Xia, Guo, Pan, Xiang and Shang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 December 2019
                : 04 March 2020
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 177, Pages: 16, Words: 13662
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                t lymphocyte,acute pancreatitis,chronic pancreatitis,pancreatic cancer,immunotherapy

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