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      Mechanisms of Immune Evasion and Immune Modulation by Lymphoma Cells

      1 , 1 , *

      Frontiers in Oncology

      Frontiers Media S.A.

      CD58, CD70, Epstein–Barr virus, HLA-G, lymphoma, microenvironment, PDL1, PD1

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          Abstract

          Purpose

          Targeting cancer cells by modulating the immune system has become an important new therapeutic option in many different malignancies. Inhibition of CTLA4/B7 and PD1/PDL1 signaling is now also being investigated and already successfully applied to various hematologic malignancies.

          Methods

          A literature review of PubMed and results of our own studies were compiled in order to give a comprehensive overview on this topic.

          Results

          We elucidate the pathophysiological role of immunosuppressive networks in lymphomas, ranging from changes in the cellular microenvironment composition to distinct signaling pathways such as PD1/PDL1 or CTLA4/B7/CD28. The prototypical example of a lymphoma manipulating and thereby silencing the immune system is Hodgkin lymphoma. Also other lymphomas, e.g., primary mediastinal B-cell lymphoma and some Epstein–Barr virus (EBV)-driven malignancies, use analogous survival strategies, while diffuse large B-cell lymphoma of the activated B-cell type, follicular lymphoma and angioimmunoblastic T-cell lymphoma to name a few, exert further immune escape strategies each. These insights have already led to new treatment opportunities and results of the most important clinical trials based on this concept are briefly summarized. Immune checkpoint inhibition might also have severe side effects; the mechanisms of the rather un(der)recognized hematological side effects of this treatment approach are discussed.

          Conclusion

          Silencing the host’s immune system is an important feature of various lymphomas. Achieving a better understanding of distinct pathways of interactions between lymphomas and different immunological microenvironment compounds yields substantial potential for new treatment concepts.

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          Most cited references 96

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          IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

          Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
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            Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.

            Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.
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              Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.

              Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
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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
                07 March 2018
                2018
                : 8
                Affiliations
                1Institute of Pathology and Medical Genetics, University Hospital of Basel , Basel, Switzerland
                Author notes

                Edited by: Matteo Bellone, San Raffaele Hospital (IRCCS), Italy

                Reviewed by: Scott Rodig, Brigham and Women’s Hospital, United States; Luis De La Cruz-Merino, Hospital Universitario Virgen Macarena, Spain

                *Correspondence: Alexandar Tzankov, alexandar.tzankov@ 123456usb.ch

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

                Article
                10.3389/fonc.2018.00054
                5845888
                Copyright © 2018 Menter and Tzankov.

                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 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.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 136, Pages: 11, Words: 9949
                Categories
                Oncology
                Review

                Oncology & Radiotherapy

                pd1, pdl1, microenvironment, lymphoma, hla-g, epstein–barr virus, cd70, cd58

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