Clinical application of immune checkpoints in targeted immunotherapy of prostate cancer

Abstract

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4⁺ and CD8⁺), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa.

Keywords: Biomarkers; Clinical trials; Co-inhibitory; Co-stimulatory; Monoclonal antibody.

Fig. 1

Potential ICP targets in PCa and their interplay with specific ligand. The interaction among negative co-inhibitory ICPs, including PD-1, CTLA-4, LAG-3, and V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA), T-cell immunoglobulin mucin 3 (TIM-3), B- and T-lymphocyte attenuator (BTLA), and B7-H3 by their specific ligand or receptor activates immunosuppression in TME. Induction of OX40, 4-1BB, ICOS, and glucocorticoid-induced TNFR family-related gene (GITR) signaling pathways in effector T cells stimulates anti-tumor immune responses. Overexpression of ICOS and GITR on T_reg cells has immune inhibitory roles in PCa. Overexpression of indoleamine-2, 3-dioxygenase (IDO) on tumor tissue and infiltrated DCs induces immunosuppression and T_reg cell activation