Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.
Cancer discovery. 2024 Dec 05 [Epub ahead of print]
Lisa N Chesner, Fanny Polesso, Julie N Graff, Jessica E Hawley, Alexis K Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S Chen, Reed M Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M Kim, Megha Bhalla, Thomas O'loughlin, Duygu Kuzuoglu-Ozturk, Junjie T Hua, Michelle L Badura, Scott Wilkinson, Shana Y Trostel, Andries M Bergman, Davide Ruggero, Charles G Drake, Adam G Sowalsky, Lawrence Fong, Matthew R Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A Quigley, Luke A Gilbert, Felix Y Feng, Amy E Moran
University of California, San Francisco, San Francisco, CA, United States., Oregon Health & Science University, Portland, OR, United States., University of Washington, Seattle, WA, United States., Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden., University Hospitals of Cleveland, Cleveland, OH, United States., Oregon Health & Science University, Portland, Oregon, United States., The Netherlands Cancer Institute, Amsterdam, North Holland, Netherlands., University of California San Francisco Medical Center, San Francisco, CA, United States., Fred Hutchinson Cancer Center, Seattle, WA, United States., University of California, San Francisco, San Francisco, United States., National Cancer Institute, Bethesda, MD, United States., National Institutes of Health, BETHESDA, MD, United States., Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands., Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, United States., University of California, San Francisco, Seattle, WA, United States., Genentech, south san francisco, CA, United States.