T cell intrinsic androgen receptor activity regulates response to immunotherapy

Abstract Immune checkpoint blockade has revolutionized the field of oncology inducing durable anti-tumor immunity in many solid tumors. In advanced prostate cancer patients, immunotherapy treatments have largely failed. Androgens have pleiotropic functions in prostate cancer; they are potent drivers of cancer cell growth and can suppress T cell function. In metastatic prostate cancer, intratumor androgen levels can remain high. Androgen deprivation therapy, the backbone of clinical care in prostate cancer, is classically administered to inhibit tumor cell growth. We postulated that this therapy also impacts tumor associated T cells. To test this hypothesis, we performed transcriptome profiling of individual leukocytes isolated from metastatic prostate cancer lesions resistant to androgen deprivation therapy (ADT) and androgen receptor (AR) antagonism and prior to treatment with a PD-1 inhibitor. We reveal that inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. Notably, AR directly bound to Ifng and eviction of this transcription factor with a small molecule significantly increased cytokine production in CD8 T cells. Furthermore, genomic deletion of Ar prevented chronically stimulated CD8 T cells from losing their ability to make IFNγ upon restimulation. Finally, we demonstrate that AR blockade sensitizes multiple tumor mouse models to effective checkpoint blockade by directly enhancing CD8 T cell function. Together, our findings establish T cell specific AR activity as one mechanism of immunotherapy resistance and show that targeting AR can improve immunotherapy outcomes. Citation Format: Amy E. Moran, Fanny Polesso, Zheng Xia, George Thomas, Julie Graff. T cell intrinsic androgen receptor activity regulates response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1301.