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IMMUNOSUPPRESSIVE NETWORKS IN THE TUMOUR ENVIRONMENT AND THEIR THERAPEUTIC RELEVANCE 高丰光 Weiping Zou NATURE REVIEWS | CANCER VOLUME 5 | APRIL 2005 | 263.

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Nat. Rev. Urol. doi:10.1038/nrurol.2018.10 Figure 3 The utility of virotherapy to achieve effective prostate cancer immunotherapy Figure 3 | The utility of virotherapy to achieve effective prostate cancer immunotherapy. The main goal of many immunotherapies is the activation of antitumour T cells, as antitumour T cell responses are associated with improved prostate cancer outcomes. The activation of an antitumour T cell requires three signals: (1) tumour-derived antigenic peptide presented in the context of a major histocompatibility complex (MHC) receptor, (2) co-stimulation, and (3) stimulatory cytokines. Immune evasion that is associated with the tumour microenvironment impairs the expression of one or more of these essential signals. a | In the absence of a therapeutic intervention, the microenvironment promotes tumour cell expression of inhibitory molecules, such as immune checkpoint receptors programmed cell death 1 ligand 1 (PDL1) or V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA), and the tumour cells lack MHC expression. As a result, T cells remain anergic and the tumour persists. b | Using currently available immune checkpoint inhibitors, such as antibodies against programmed cell death protein 1 (PD1), T cells can be rescued and activated to cause immune-mediated tumour cell death. However, other microenvironment-associated suppressive mechanisms, such as reduced MHC expression or co-stimulation of antigen-presenting cells (APCs), remain intact, resulting in suboptimal effectiveness of checkpoint inhibitor therapies in prostate cancer. c | Oncolytic viruses can overcome the microenvironment-associated immune suppression and promote antitumour T cell responses. However, oncolytic viruses do not alter the immune dysregulation imparted by immune checkpoint molecules. d | When applied in combination, oncolytic viruses can overturn the immunosuppression and initiate antitumour immune responses while immune checkpoint inhibitors address the checkpoint-molecule-mediated immune dysregulation. This combination strategy has the potential to deliver optimal immunotherapeutic benefits and improve therapeutic effectivity against prostate cancer in the clinics. TCR, T cell receptor. Lee, P. & Gujar, S. (2018) Potentiating prostate cancer immunotherapy with oncolytic viruses Nat. Rev. Urol. doi:10.1038/nrurol.2018.10