Review Article | Published:

Potentiating prostate cancer immunotherapy with oncolytic viruses

Nature Reviews Urology volume 15, pages 235250 (2018) | Download Citation

Abstract

The clinical effectiveness of immunotherapies for prostate cancer remains subpar compared with that for other cancers. The goal of most 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 breakthrough in prostate cancer immunotherapy.

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 reprogramming of the tumour microenvironment can be exploited in strategic treatment combinations to achieve improved effectiveness of otherwise subpar cancer immunotherapies, including those based on immune checkpoint inhibitors

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Acknowledgements

S.G. and 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

Affiliations

  1. Department of Pathology and Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.

    • Patrick Lee
    •  & Shashi Gujar
  2. Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, Nova Scotia B3K 6R8, Canada.

    • Shashi Gujar

Authors

  1. Search for Patrick Lee in:

  2. Search for Shashi Gujar in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Patrick Lee or Shashi Gujar.

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.

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DOI

https://doi.org/10.1038/nrurol.2018.10