Part of the Joint Division of Cancer – CRUK Convergence Science Seminar Series, Thursday 18.07.24 @ 15.00, hosted by Professor Charlotte Bevan.

We are delighted to have Dr Lisa Chesner who earned her PhD from the University of Minnesota-Twin Cities in the Department of Pharmacology,  and joined Dr. Felix Feng’s lab as a postdoctoral scholar in the Department of Radiation Oncology at the University of California, San Francisco, (UCSF) in 2018. Her research utilizes whole-genome CRISPRi screening technology to better understand the molecular drivers of prostate cancer and improve treatment options for patients. She is a Prostate Cancer Foundation Young Investigator and recipient of a Department of Defense Early Investigator Award, which focuses on understanding the regulation of MHC Class I and immune evasion in advanced prostate cancer.

Summary of Talk

One mechanism by which cancer cells facilitate immune escape and immunotherapy resistance is through downregulation of the major histocompatibility complex (MHC) Class I, which plays a pivotal role in the adaptive immune response by presenting tumor-associated antigens on the surface of cancer cells to CD8 T cells. Loss of MHC Class I is associated with more aggressive disease and immune evasion in prostate cancer. However, the molecular mechanisms that control MHC Class I downregulation in prostate cancer remain unknown. We conducted a whole-genome CRISPRi flow cytometry screen to identify regulators of MHC Class I in prostate cancer. Knockdown of the androgen receptor (AR) resulted in the most substantial increase in MHC Class I expression. AR inhibition increased MHC Class I expression in vitro, improved T cell response in co-culture models, and increased antigen presentation and T cell anti-tumor immunity in vivo. Patient data from phase II clinical trials also confirmed that decreased AR activity and increased MHC Class I expression were associated with immunotherapy response. Overall, our data show that AR suppresses MHC Class I expression, and that androgen-targeted therapies improve antigen presentation and T cell mediated immunity.