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      The future of cancer immunotherapy: microenvironment-targeting combinations

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          Abstract

          Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.

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          Regulatory T cells in cancer immunotherapy

          Atsushi Tanaka, Shimon Sakaguchi (2017)
          FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective.
          Article 0 comments Cited 730 times – based on 0 reviews     Review now
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            Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

            Shohei Koyama, Esra A Akbay, Yvonne Y. Li … (2016)
            Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
            Article 0 comments Cited 686 times – based on 0 reviews     Review now
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              Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells.

              Beatriz Carreno, Vincent Magrini, Michelle Becker-Hapak … (2015)
              T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.
              Article 0 comments Cited 572 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jedd D. Wolchok:
                ORCID: http://orcid.org/0000-0001-6718-2222
                wolchokj@mskcc.org
                Journal
                Journal ID (nlm-ta): Cell Res
                Journal ID (iso-abbrev): Cell Res
                Title: Cell Research
                Publisher: Springer Singapore (Singapore )
                ISSN (Print): 1001-0602
                ISSN (Electronic): 1748-7838
                Publication date (Electronic): 28 May 2020
                Publication date PMC-release: 28 May 2020
                Publication date (Print): June 2020
                Volume: 30
                Issue: 6
                Pages: 507-519
                Affiliations
                [1 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Department of Medicine, , Memorial Sloan Kettering Cancer Center, ; New York, NY 10065 USA
                [2 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Human Oncology and Pathogenesis Program, , Memorial Sloan Kettering Cancer Center, ; New York, NY 10065 USA
                [3 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medicine, ; New York, NY 10065 USA
                [4 ]GRID grid.489192.f, Parker Institute for Cancer Immunotherapy, ; San Francisco, CA USA
                Author information
                http://orcid.org/0000-0001-6422-2997
                http://orcid.org/0000-0001-6718-2222
                Article
                Publisher ID: 337
                DOI: 10.1038/s41422-020-0337-2
                PMC ID: 7264181
                PubMed ID: 32467593
                SO-VID: 0b4868b5-4f6e-437f-acce-55bd8005e577
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 13 January 2020
                Date accepted : 29 April 2020
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © Center for Excellence in Molecular Cell Science, CAS 2020

                ScienceOpen disciplines: Cell biology
                Keywords: cancer microenvironment,cancer immunotherapy
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: cancer microenvironment, cancer immunotherapy

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