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.

Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer

“…Nevertheless, no anti-tumor response can be triggered due to the immunosuppressive TME (15). Indeed, a lower density of immune cells has been observed in prostatic adenocarcinomas compared to benign nodular hyperplasia of the prostate (16). Anti-tumor CD8+ T cells are also suppressed by the depletion of arginase and tryptophan from the TME after upregulation of secretion of nitrous oxide synthase and indoleamine 2,3-dioxygenase (IDO) by myeloid-derived suppressor cells (MDSCs) (16), or by the presence of a large amount of regulatory T cells (Tregs) compared to other cancers (17), and other immunosuppressive cells Abbreviations: APC, antigen-presenting cell; bsAb, bispecific antibodies; BT, brachytherapy; CAR, chimeric antigen receptor; CSF1, colony-stimulating factor 1; CTLA-4, cytotoxic T lymphocyte antigen; cTL, cytotoxic T lymphocyte; DC, dendritic cell; DHT, dihydrotestosterone; EBRT, external beam radiation therapy; EORTC, European Organization for Research and Treatment of Cancer; EMT, epithelial-mesenchymal transition; ESTRO, European Society for Radiotherapy and Oncology; EV, extracellular vesicle; HIF-1, hypoxia-inducible factor 1; HLA, human leukocyte antigen; HR, hazard ratio; ICI, immune checkpoint inhibitors; IFN, interferon; mCRPC, metastatic castration-resistant prostate cancer; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; miRNA, microRNA; NK, natural killer; NKT, natural killer T; ORR, objective response rate; PAP, prostatic acid phosphatase; PCa, prostate cancer; PD-1, programmed cell death 1; PD-L1/2, programmed cell death-ligand 1/2; POLD1, DNA polymerase delta; POLE, polymerase epsilon; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; SABR, stereotactic ablative radiotherapy; SBRT, Stereotactic body radiation therapy; T, T lymphocyte; TAA, tumor associated antigen; TAM, tumor associated macrophage; TCR, t cell receptor; TEX, tumor exosome; TIL, tumor infiltrating lymphocyte; TMB, tumor mutational burden; TME, tumor microenvironment; T reg, regulatory T cell; TSA, tumor specific antigen; VSV, vesicular stomatitis virus.…”

“…Indeed, a lower density of immune cells has been observed in prostatic adenocarcinomas compared to benign nodular hyperplasia of the prostate ( 16 ). Anti-tumor CD8+ T cells are also suppressed by the depletion of arginase and tryptophan from the TME after upregulation of secretion of nitrous oxide synthase and indoleamine 2,3-dioxygenase (IDO) by myeloid-derived suppressor cells (MDSCs) ( 16 ), or by the presence of a large amount of regulatory T cells (Tregs) compared to other cancers ( 17 ), and other immunosuppressive cells such as M2 TAM or neutrophils, both associated with poor survival ( 18 ). This immunosuppressive environment is promoted by specific factors such as TGF-β ( 19 ) and CXCR2 ( 20 ) secreted under the TME.…”

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

“…Moreover, tumor development occurs in a whole organism with physiological processes conserved. However, we now know the major importance of the immune system in cancer development [53,54]. Additionally, as most of the xenografted cells are of human origin, immunodeficient mice are used as a recipient to avoid cell elimination by the mouse immunity system.…”

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

“…In order to best overcome the resistance to immunotherapies in the setting of advanced PCa, it is critical to understand the mechanisms that lead to immune resistance in the context of the cellular components of the TME that potentiate immunosuppression and the molecules and genetic pathways that facilitate continued tumor growth [9]. Some of these key immune resistance mechanisms that will be explored include altered MHC molecule expression, decreased TMB, loss of tumor suppressor proteins, abberant androgen receptor signaling as well as increased infiltration of immune-suppressive cell types (i.e., T-regulatory cells, myeloid-derived suppressor cells) in the TME [9,17,18].…”