The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer

Abstract

Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a “cold” tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.

Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment

“… 14–16 Various immunosuppressive cell subtypes are also present in the tumor microenvironment (TME) in prostate cancer, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which can inhibit the function of immune effector cells. 17 MDSC have been identified as a key factor in establishing immunosuppressive and tumor-promoting TME in prostate cancer. 18 The abundance of MDSCs in the blood of patients with prostate cancer correlates with disease burden and circulating prostate-specific antigen(PSA) levels.…”

The Role of ERα and ERβ in Castration-Resistant Prostate Cancer and Current Therapeutic Approaches

“…Docetaxel, prednisone, and cabazitaxel are potent inhibitors of microtubule depolymerization. The activity of cabazitaxel is resistant to P glycoprotein, the adenosine triphosphate (ATP)-dependent drug efflux pump that is sometimes expressed in cancer cells [ 97 ]. Meanwhile, AA is a highly selective, potent inhibitor of the cytochrome P450 17A1 (CYP17A1) enzyme, which leads to a decrease in the proliferation of PCa cells [ 85 ].…”

Stand der Forschung und neue therapeutische Perspektiven in der Immuntherapie des Prostatakarzinoms

“…Pembrolizumab wurde in Phase-I- und Phase-II-Studien bei neu diagnostizierten oligometastasierten mHSPC-Patienten oder bei mCPRC-Patienten in Kombination mit Kryotherapie, mit ADXS31-142 (einem Krebsimpfstoff, der einen abgeschwächten Lebendstamm von Listeria monocytogenes enthält, der für ein PSA-Fusionsprotein und ein Fragment von Listeriolysin O kodiert) und mit MVI-816 (einem DNA-Impfstoff, der für die PAP kodiert) untersucht [161, 187–190].…”