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

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.

DNA methyltransferase inhibition promotes recruitment of myeloid-derived suppressor cells to the tumor microenvironment through induction of tumor cell-intrinsic interleukin-1

“…ns = non-significant; ***P < 0.0001; *P < 0.01. tumor responses to DNMT inhibitor were less potent in inducing chemokine expression and did not promote MDSC recruitment. The latter is supported by findings demonstrating that IFN generally represses recruitment of MDSCs to the TME [15,51]. Together, these findings suggest that the tumor response to DNMT inhibitors may be determined by the relative involvement of IFN and IL-1 signaling and the recruitment of MDSCs to the TME.…”

Initial Myeloid Cell Status Is Associated with Clinical Outcomes of Renal Cell Carcinoma

“…IL-1β and IL-8 are involved in the recruitment of MDSC in patients with RCC [25,26]. It has been reported that MCP-1 induces MDSC accumulation [27], whereas INF-α2 suppresses MDSC accumulation [28]. Plasma levels of INF-γ and IL-10 are found to be correlated to immune-related adverse events after ICI therapy [29,30].…”

Natural killer cell activity in metastatic castration resistant prostate cancer patients treated with enzalutamide

“…While the androgen receptor still plays a crucial role in the development of castration resistance, changes in immune cells were also observed to have a distinctive action during transmission of PC disease to mCRPC 33 . It’s well known that PC and especially the late stage of the disease, CRPC, have a very complex immunosuppressive tumor microenvironment 34 .…”