How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer

Abstract

Background: Advanced prostate cancer remains one of the most common and deadly cancers, despite advances in treatment options. Immunotherapy has provided little benefit to a majority of patients, largely due to the immunosuppressive tumor microenvironment that gives rise to inherently "cold tumors". In this review, we discuss the immunopathology of the prostate tumor microenvironment, strategies for treating prostate cancer with immunotherapies, and a perspective on potential approaches to enhancing the efficacy of immunotherapies.

Methods: Databases, including PubMed, Google Scholar, and Cochrane, were searched for articles relevant to the immunology of prostate cancer. We discuss the impact of different types of treatments on the immune system, and potential mechanisms through which prostate cancer evades the immune system.

Results: The tumor microenvironment associated with prostate cancer is highly immunosuppressive due to (1) the function of regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSCs), (2) the cytokine milieu secreted by tumor stromal cells and fibroblasts, and (3) the production of adenosine via prostatic acid phosphatase. Both adenosine and tumor growth factor beta (TGF-beta) serve as potent immunosuppressive molecules that could also represent potential therapeutic targets. While there have been many immunotherapy trials in prostate cancer, the majority of these trials have targeted a single immunosuppressive mechanism resulting in limited clinical efficacy. Future approaches will require the integration of improved patient selection as well as use of combination therapies to address multiple mechanisms of resistance.

Conclusion: Prostate cancer inherently gives rise to multiple immunosuppressive mechanisms that have been difficult to overcome with any one immunotherapeutic approach. Enhancing the clinical activity of immunotherapies will require strategic combinations of multiple therapies to address the emerging mechanisms of tumor immune resistance.

Fig. 1. Interactions in the tumor microenvironment and effects of therapies.

A2A/BR adenosine 2A/2B receptor, CCL22 C-C motif chemokine 22, CTLA-4 cytotoxic T lymphocyte-associated protein 4, IDO indoleamine 2,3-dioxygenase, IL-10 interleukin 10, MDSCs myeloid-derived suppressor cells, NOS nitric oxide synthase, PAP prostatic acid phosphatase, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, PGE2 prostaglandin E2, TAMs tumor-associated macrophages, TGF-ß tumor growth factor beta, VEGF vascular endothelial growth factor. Shown here are some of the numerous interactions in the tumor microenvironment, both inhibitory and stimulatory, between different cell types, the cytokines and chemokines they produce, the local immune cells, and the many therapies used to treat prostate cancer, as detailed above.