Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment

Abstract

Prostate cancer is the second most common cause of cancer-related death in men in the United States and the fifth worldwide. Most prostate cancer arises as an androgen-dependent tumor but eventually progresses into castration-resistance prostate cancer, incurable by the current androgen deprivation therapy and chemotherapy. The development of immunotherapy in cancer treatment has brought an exciting era of antiprostate cancer therapy through antitumor immune responses. Prostate cancer is recognized as a poorly immunogenic tissue with immunological ignorance showing low levels of antigen-presenting process and cytotoxic T-cell activation, high levels of immune checkpoint molecules and immunosuppressive cytokines/chemokines, and recruitment of immunosuppressive cells. Immunotherapies for prostate cancer have been developed to activate the innate and adaptive immune responses, such as vaccines and adoptive CAR-T cells, or to inhibit immunosuppressive molecules, such as immune checkpoint inhibitors or antibodies. The U.S Food and Drug Administration has approved Sipuleucel-T for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross-interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients.

Trial registration: ClinicalTrials.gov NCT00323882.

Keywords: cancer vaccines; castration-resistant prostate cancer; immune checkpoint inhibitors; immunosuppression; immunotherapy.