Type I Interferon Promotes Antitumor T Cell Response in CRPC by Regulating MDSC

SIMPLE SUMMARY: Despite initial tumor regression following androgen blockade treatment, relapse of castration-resistant prostate cancer (CRPC) eventually occurs in most patients. Immunotherapy aims to activate the host immune system to fight against cancer and has achieved significant therapeutic effects in various solid tumors. The purpose of our research was to investigate the mechanisms underlying the immune response during CRPC development and to screen effective immunotherapies against CRPC. We found that interferon-α (IFNα) directly inhibited the progression of CRPC, reduced the accumulation of the immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) in the tumor microenvironment (TME), and impaired the inhibitory function of G-MDSCs on T cell activation. This research provides a potential strategy for the clinical treatment of CRPC. ABSTRACT: Background: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among prostate cancer patients. Here, our aim was to ascertain the immune regulatory mechanisms involved in CRPC development and identify potential immunotherapies against CRPC. Methods: A CRPC model was established using Myc-CaP cells in immune-competent FVB mice following castration. The immune cell profile of the tumor microenvironment (TME) was analyzed during CRPC development. Different immunotherapies were screened in the CRPC tumor model, and their efficacies and underlying mechanisms were investigated in vitro and in vivo. Results: During CRPC development, the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the TME increased. Among the immunotherapies tested, IFNα was more effective than anti-PD-L1, anti-CTLA-4, anti-4-1BB, IL-2, and IL-9 in reducing Myc-CaP CRPC tumor growth. IFNα reduced the number of G-MDSCs both in vitro during differentiation and in vivo in CRPC mice. Furthermore, IFNα reduced the suppressive function of G-MDSCs on T cell proliferation and activation. Conclusion: G-MDSCs are crucial to effective immunotherapy against CRPC. Treatment with IFNα presents a promising therapeutic strategy against CRPC. Besides the direct inhibition of tumor growth and the promotion of T cell priming, IFNα reduces the number and the suppressive function of G-MDSCs and restores T cell activation.