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      Senescent T cells: a potential biomarker and target for cancer therapy

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          Abstract

          The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

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          Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

          Flávia Castro, Ana Patrícia Cardoso, Raquel Gonçalves … (2018)
          Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.
          Article 0 comments Cited 508 times – based on 0 reviews     Review now
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            T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

            Enfu Hui, Jeanne Cheung, Jing Zhu … (2017)
            Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.
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              Mechanisms and functions of cellular senescence

              Nicolás Herranz, Jesus Gil (2018)
              Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non–cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.
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                Author and article information

                Contributors
                Lixiang Xue
                Hongyan Guo
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 25 May 2021
                Publication date Collection: June 2021
                Publication date (Electronic): 25 May 2021
                Volume: 68
                Electronic Location Identifier: 103409
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Peking University Third Hospital, China
                [2 ]Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
                [3 ]Biobank, Peking University Third Hospital, Beijing, China.
                Author notes
                [#]

                These authors contributed equally to this work

                Article
                Publisher Item ID: S2352-3964(21)00202-4 Publisher ID: 103409
                DOI: 10.1016/j.ebiom.2021.103409
                PMC ID: 8170103
                PubMed ID: 34049248
                SO-VID: 48d6bf15-7d13-466a-a614-a33b37cc3f43
                Copyright © © 2021 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 19 February 2021
                Date revision received : 9 April 2021
                Date accepted : 6 May 2021
                Categories
                Subject: Review

                Keywords: senescent t cell,tumour microenvironment,cancer immunotherapy,prognostic biomarkers,therapeutic targets
                Data availability:
                Keywords: senescent t cell, tumour microenvironment, cancer immunotherapy, prognostic biomarkers, therapeutic targets

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