Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

SIMPLE SUMMARY: The mainstay of treatment for advanced prostate cancer (PCa) is androgen deprivation therapy (ADT), and although patients initially respond, almost all will eventually develop progressive and metastatic disease. Metastatic, hormone-resistant prostate cancer is essentially incurable. A key problem with ADT is that it is not effective in the long term, partly due to the fact that prostate cancers can switch from requiring androgen to grow to surviving without it and these new tumor cells are more sensitive to stress hormones released by the brain as a consequence of chronic stress/depression. Moreover, both extensive treatment with ADT and chronic stress/depression lead to the recruitment of immature myeloid-derived suppressor cells (MDSCs) which are known to suppress immune responses against tumors. The future of prostate cancer treatments will most certainly include a combination of vaccine with beta-blockers (to interfere with signals from stress hormones) and/or the use of histone deacetylase (HDAC) inhibitors which prevent the function/recruitment of MDSC where timing will be of critical importance. ABSTRACT: Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients.