A Perspective of Immunotherapy for Prostate Cancer

Abstract

In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa.

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…Indeed, such receptor, expressed on the surface of both TCD8+ and TCD4+ lymphocytes (T-cells) as well as of regulatory immunosuppressive T cells (Tregs), competitively acts towards T cell CD28 co-receptor that, instead, mainly works for T-cell immune function activation. Both CTLA-4 and CD28 receptors can bind two ligand proteins, B7-1 and B7-2 -made from antigen-presenting cells (APCs) -towards which CTLA-4 receptor shows higher affinity than the CD28 one (5,7). It results that CTLA-4 is one of the most powerful immunosuppressive molecular factor on T-cell surface.…”

“…Unfortunately, as regards advanced PCa treatment, among seventeen CRPC patients enrolled in the human IgG4-mediated anti-PD-1 mAb nivolumab trial, only one achieved just a 28% tumor load reduction, without significant other immune responses (5,11,(17)(18)(19)(20). In this regard, highly increased levels of PD-L1 on PC cells are, indeed, a poor prognostic marker given the easy onset of PCa adaptive immune resistance.…”

“…The interaction between PD-1 and PCa cell surface-expressed PD-L1/ PD-L2 ligands can induce a decrease in antitumor immune response, with further PCa progression and metastatic spread (4,5,9,11,15). PD-L1 is over-expressed on both PCa cells and tumor microenvironmental stromal cells, that's why it follows that, because of high PD-1/PD-L1 interaction, the immune response goes down with increase in cancer cell proliferation (16).…”

“…@ C I C E d i z i o n i I n t e r n a z i o n a l i results in enhancing anti-tumor immune response with consequent effective challenges against tumor progression/recurrence. Ipilimumab, as a fully human IgG1k-based anti-CTLA-4 mAb -the first immune check point blocker taking role in oncology clinical trials -has been used either alone or in combination with conventional therapies (ADT, radiation, chemotherapy) in several clinical trials for metastatic castration-resistant prostate cancer (mCRPC) patients, it resulting a significant decrease in PSA serum levels (4,5,11,12). Moreover, from a trial concerning combination therapy of T-cell check point modulator ipilimumab with EBRT it was followed that the radiation exposure, besides not inducing immunosuppressive effects, can, instead, synergically act with ipilimumab to effectively increase the antitumor immune response (4,5,(11)(12)(13).…”

“…It results that CTLA-4 is one of the most powerful immunosuppressive molecular factor on T-cell surface. In addition, Tregs can make easier the drop of immune responses also by release of both interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) immunosuppressive agents (4)(5)(6)(7)(8)(9)(10). Since the CTLA-4 link with tumor cell B7-1/B7-2 ligands can suppress T-cell immune responsiveness, it follows that the disruption of CTLA-4 activity by anti-CTLA-4 mAbs (so-called immune T-cell check point modulators) can Active immunotherapy, triggering the host immune system to focusly target cancer cells.…”