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2021 Robert and Cindy Citrone-PCF VAlor Young Investigator Award

Investigating Mechanisms of Androgen Mediated T cell Suppression in High-Risk Prostate Cancer

Amy Moran, PhD
Oregon Health & Science University

Mentor: Lisa Coussens, PhD

Description:

  • Men and women have striking differences in their risk for autoimmune diseases, susceptibility to many cancers, and response to some pathogens, such as SARS-COV2.
  • In males, testosterone is the most common androgen and is implicated in dampening immune responses, resulting in higher viral titers and increased cancer-associated mortality, yet is protective in autoimmunity.
  • Notably, prostate cancer is largely refractory to immunotherapy and tumor cells are a local source of androgens. Whether or not androgens suppress anti-tumor immunity or the efficacy of immunotherapies in prostate cancer patients is unknown.
  • Dr. Amy Moran is studying the mechanisms of immunotherapy resistance in prostate cancer patients, and how androgens or the androgen receptor (AR) contribute.
  • In a clinical trial, Dr. Moran and colleagues observed that responses to enzalutamide + anti-PD1 immunotherapy were higher in patients with lower AR activity in T cells. The team further demonstrated that AR prevents expression of T cell activation genes, and that treatment with enzalutamide + anti-PD1 synergistically activated T cells.
  • In this project, Dr. Moran will determine whether androgens within the prostate tumor microenvironment repress T cell mediated anti-tumor immunity.
  • The impact of AR inhibition on T cell function will be evaluated by comparing T cells within tumors with those adjacent to the tumor in prostate cancer biopsy samples.
  • The gene expression landscape of T cells after genetic deletion or pharmacologic inhibition of AR activity will be investigated.
  • If successful, this project will reveal how androgens and AR activity regulate human T cell function and immunotherapy resistance and may reveal novel therapeutic approaches to reduce hormone-mediated immune suppression.

What this means to patients: Androgens have a suppressive effect on T cells and may underlie why patients with prostate cancer typically have poor responses to immunotherapy. Dr. Moran will define the biology of androgen and AR functions in T cells in prostate cancer patients, which will lead to improved therapeutic strategies combining AR-targeted therapy with immunotherapy.