Sequencing TILs from patients with metastatic castration-resistant prostate cancer (mCRPC), Guan, Polesso, and Wang et al. identified an intratumoral CD8+ T cell gene signature in anti-PD-1 responders highlighted by AR deactivation. This signature correlated negatively with AR activity and positively with IFNγ in both mCRPC and melanoma patient cohorts. AR directly bound Ifng and Gzmb open chromatin regions on CD8+ T cells, and AR knockout or androgen deprivation restored IFNγ production. In an ICB-refractory mouse tumor model, androgen deprivation with anti-PD-L1 boosted CD8+ T cell IFNγ/GzmB production and extended survival.
Contributed by Alex Najibi
ABSTRACT: Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.
Author Info: (1) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA. Molecular Microbiology and Immunology, Oregon Health and Science University, Port
Author Info: (1) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA. Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. Genentech, Inc., South San Francisco, CA, USA. (2) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (3) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. Bristol Myers Squibb, New Brunswick, NJ, USA. (4) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (5) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (6) Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. Department of Biology, University of Portland, Portland, OR, USA. (7) Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA. (8) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (9) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. Department of Radiation Medicine, Oregon Health and Science University, Portland, OR, USA. VA Portland Health Care System, Portland, OR, USA. (10) VA Portland Health Care System, Portland, OR, USA. (11) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (12) Clinical IO Discovery, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA. (13) Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. VA Portland Health Care System, Portland, OR, USA. (14) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA. Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (15) Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. moranam@ohsu.edu. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. moranam@ohsu.edu.
