KEY POINTS * Immunologically, prostate cancer is amenable to currently available, as well as emerging, cancer immunotherapies * Tumour-associated immunosuppressive mechanisms restrict the

development of antitumour immune responses and are the largest barrier to the effectiveness of immunotherapies for prostate cancer * Oncolytic viruses can target prostate cancer through

three mechanisms: direct killing of tumour cells through oncolysis, destruction of the tumour vasculature, and initiation of antitumour immunity * Oncolytic viruses can override

tumour-associated immunosuppressive mechanisms and create an environment conducive to the development of antigen-specific and protective antitumour immunity * Oncolytic-virus-induced

immunotherapies is the activation of immune effectors, such as T cells and natural killer cells, as the presence of these activated mediators positively correlates with patient outcomes.

Clinical evidence shows that prostate cancer is immunogenic, accessible to the immune system, and can be targeted by antitumour immune responses. However, owing to the detrimental effects of

prostate-cancer-associated immunosuppression, even the newest immunotherapeutic approaches fail to initiate the clinically desired antitumour immune reaction. Oncolytic viruses, originally

used for their preferential cancer-killing activity, are now being recognized for their ability to overturn cancer-associated immune evasion and promote otherwise absent antitumour immunity.

This oncolytic-virus-induced subversion of tumour-associated immunosuppression can potentiate the effectiveness of current immunotherapeutics, including immune checkpoint inhibitors (for

example, antibodies against programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1), and cytotoxic T lymphocyte antigen 4 (CTLA4)) and chemotherapeutics that induce

immunogenic cell death (for example, doxorubicin and oxaliplatin). Importantly, oncolytic-virus-induced antitumour immunity targets existing prostate cancer cells and also establishes

long-term protection against future relapse. Hence, the strategic use of oncolytic viruses as monotherapies or in combination with current immunotherapies might result in the next

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PROSTATE CANCER Article 06 March 2023 REOVIRUS MUTANT JIN-3 EXHIBITS LYTIC AND IMMUNE-STIMULATORY EFFECTS IN PRECLINICAL HUMAN PROSTATE CANCER MODELS Article Open access 16 June 2021

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P.L. are supported by grants from Prostate Cancer Canada, Canadian Institutes of Health Research (CIHR), Terry Fox Research Institute (TFRI), and Canadian Cancer Research Institute (CCSRI).

The authors thank Y. Kim for her help with graphics and manuscript preparation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pathology and Department of Microbiology and

Immunology, Dalhousie University, Halifax, B3H 1X5, Nova Scotia, Canada Patrick Lee & Shashi Gujar * Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre,

Halifax, B3K 6R8, Nova Scotia, Canada Shashi Gujar Authors * Patrick Lee View author publications You can also search for this author inPubMed Google Scholar * Shashi Gujar View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.G. researched data for the article and wrote the manuscript. Both authors made substantial

contributions to discussion of the article content and reviewed and/or edited the manuscript before submission. CORRESPONDING AUTHORS Correspondence to Patrick Lee or Shashi Gujar. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3

POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR TABLE 2 GLOSSARY * Oncolytic viruses Viruses that preferentially infect and kill cancer cells ('onco' means cancer;

'lytic' means killing). * Tumour microenvironment The milieu in which the tumour resides, consisting of malignant cells and nonmalignant cells, including stromal and immune cells.

* Myeloid-derived suppressor cells (MDSCs). The heterogeneous population of myeloid cells that suppress the functions of various immune cells, especially natural killer cells and T cells,

through direct or indirect mechanisms. * Lactic acid A metabolite that has the capacity to suppress the functions of immune mediators when produced as an aberrant by-product of cancer

metabolism. * Tumour immune evasion Cancers employ various suppressive mechanisms to resist the development of antitumour immune activities and, thus, evade immune-mediated attack and

elimination. * Immune checkpoint inhibitors Agents that inhibit the interactions between immune checkpoint molecules on tumour cells and their receptors on immune cells, releasing the

inhibitory signal and enabling tumour-directed immune responses. * MHC ligands Peptides that are presented in the antigen presentation groove of major histocompatibility complex (MHC) class

I and class II molecules; this ligand-bound MHC complex is recognized by T cell receptors in a highly specific manner. * Immunologically privileged site Anatomical sites or locations, such

as the brain or eyes, that contain impaired or modified lymphatic drainage and immune surveillance are privileged against immune-response-induced collateral tissue damage. * Autoantibodies

Antibodies that are specific against an individual's own proteins and antigens. * Epithelial–mesenchymal transition A biological process through which epithelial cells lose their

characteristic cell polarity and adhesion properties and acquire a migratory and invasive phenotype similar to that of mesenchymal cells. * Cancer stem cells Cancer cells that are

pluripotent and have self-renewal capacity and, thus, possess stem-cell-like characteristics. * Neuroendocrine tumours Tumours that arise from neuroendocrine cells, which are specialized

cells that often produce hormones under neuronal control. * T cell anergy A state in which T cells remain tolerant or dysfunctional. * Immunogenic cell death A form of cell death that is

accompanied by the expression of molecules that lead to the activation of dendritic cells, which subsequently prime T cells. * Tumour-associated antigens These antigens are often

preferentially expressed on tumours but can also be found in normal tissues, whereas tumour-specific antigens are usually expressed specifically in tumours, often arising from mutations or

virally encoded oncoproteins. * Autophagy A 'self-eating' homeostatic cellular process in which damaged organelles are digested under normal physiological situations and in which,

during stress conditions, macromolecules, such as nucleic acids and amino acids, are recycled. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lee, P.,

Gujar, S. Potentiating prostate cancer immunotherapy with oncolytic viruses. _Nat Rev Urol_ 15, 235–250 (2018). https://doi.org/10.1038/nrurol.2018.10 Download citation * Published: 13

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