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      Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

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          Abstract

          Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine.

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          Most cited references79

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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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            Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

            PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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              Tertiary lymphoid structures in the era of cancer immunotherapy

              Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                09 July 2020
                July 2020
                : 9
                : 7
                : 1645
                Affiliations
                [1 ]Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; ytakeda26@ 123456gesurg.med.osaka-u.ac.jp (Y.T.); momokitakaze@ 123456gmail.com (M.K.); aasai@ 123456cfs.med.osaka-u.ac.jp (A.A.); mkonno@ 123456cfs.med.osaka-u.ac.jp (M.K.); t.arai@ 123456unitech-op.com (T.A.); toru@ 123456kyowakai.com (T.K.); oof21443@ 123456ideacon.co.jp (K.O.); yabumoto.masami@ 123456gmail.com (M.Y.); hirotsu@ 123456hbio.jp (T.H.); ydoki@ 123456gesurg.med.osaka-u.ac.jp (Y.D.); heguchi@ 123456gesurg.med.osaka-u.ac.jp (H.E.)
                [2 ]Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; s-kobayashi@ 123456umin.ac.jp (S.K.); dyamada@ 123456gesurg.med.osaka-u.ac.jp (D.Y.); hakita@ 123456gesurg.med.osaka-u.ac.jp (H.A.)
                [3 ]Artificial Intelligence Research Center, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan; taniguti@ 123456sanken.osaka-u.ac.jp
                [4 ]Unitech Co., Ltd., Kashiwa 277-0005, Japan
                [5 ]Kyowa-kai Medical Corporation, Osaka 540-0008, Japan
                [6 ]Prophoenix Division, Food and Life-Science Laboratory, Idea Consultants, Inc., Osaka-city, Osaka 559-8519, Japan
                [7 ]Kinshu-kai Medical Corporation, Osaka 558-0041, Japan
                [8 ]Hirotsu Bio Science Inc., Tokyo 107-0062, Japan
                [9 ]Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Santo Andrea Hospital, via di Grottarossa, 1035-00189 Rome, Italy; andrea.vecchione@ 123456uniroma1.it
                Author notes
                [* ]Correspondence: hishii@ 123456gesurg.med.osaka-u.ac.jp ; Tel.: +81-(0)6-6210-8406 (ext. 8405); Fax: +81-(0)6-6210-8407
                Author information
                https://orcid.org/0000-0002-7434-2316
                Article
                cells-09-01645
                10.3390/cells9071645
                7408222
                32659892
                cb89a2b3-3e71-43b2-b898-117de15c3a2a
                © 2020 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
                : 22 May 2020
                : 05 July 2020
                Categories
                Review

                exosome,cancer,immunology,surgery
                exosome, cancer, immunology, surgery

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