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      Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

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          Abstract

          Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.

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          Most cited references155

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          Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

          To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single cell analysis of the tumor, non-involved lung and blood cells together with multiplex tissue imaging to assess spatial cell distribution, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Comparing single tumor cells with adjacent normal tissue and blood from patients with lung adenocarcinoma charts early changes in tumor immunity and provides insights to guide immunotherapy design.
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            Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity

            Chimeric antigen receptors (CARs) significantly enhance anti-tumor activity of immune effector cells. While most studies have evaluated CAR-expression in T cells, here we evaluate different CAR constructs that improve natural killer (NK) cell-mediated killing. We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling. NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared to T-CAR expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR expressing cells. Using an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared to PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. Additionally, NK-CAR-iPSC-NK cells demonstrate similar in vivo activity as T-CAR-expressing T cells, though with less toxicity. These NK-CAR-iPSC-NK cells now provide standardized, targeted “off the shelf” lymphocytes for anti-cancer immunotherapy. Natural killer (NK) cells are a key part of the immune system’s ability to mediate anti-cancer activity. Kaufman and colleagues utilize human iPSCs to produce NK cells with novel chimeric antigen receptors that specifically target cancer cells in an antigen-specific manner to improve survival in an ovarian cancer xenograft model.
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              Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells.

              In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector-mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A-depleted tumors. NK cells from LDH-A-depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                21 January 2020
                2019
                : 10
                : 3038
                Affiliations
                [1] 1Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù , Rome, Italy
                [2] 2Department of Biology, University of Pisa , Pisa, Italy
                [3] 3Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù , Rome, Italy
                Author notes

                Edited by: Anahid Jewett, University of California, Los Angeles, United States

                Reviewed by: Robin Parihar, Baylor College of Medicine, United States; Robert J. Canter, University of California, Davis, United States

                *Correspondence: Loredana Cifaldi loredana.cifaldi@ 123456opbg.net

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

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2019.03038
                6985149
                32038612
                669b75bd-ee3d-4399-976a-b4eecf1945e7
                Copyright © 2020 Melaiu, Lucarini, Cifaldi and Fruci.

                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
                : 13 August 2019
                : 11 December 2019
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 210, Pages: 18, Words: 14533
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Funded by: Ministero della Salute 10.13039/501100003196
                Categories
                Immunology
                Mini Review

                Immunology
                natural killer cells,tumor microenvironment,solid tumors,immune checkpoint inhibitors,cellular metabolism,cancer stem cells,hypoxia,adoptive transfer of nk and car-nk cells

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