Sex differences in disease are well characterized, with males being more susceptible to infections and cancers, and females more susceptible to autoimmune diseases. Notably, males were 20% more likely to die from COVID-19 than females. Men are also more susceptible to most cancers including leukemia, lung cancer, and melanoma and have an overall higher incidence of cancer-related death. Conversely, females represent approximately 80% of individuals diagnosed with autoimmunity – a disease where the immune system attacks itself. Despite these sex differences, the question remains unanswered how sex hormones directly regulate immune responses or cancer therapy outcomes. This gap in knowledge is astounding when we consider that cancer immunotherapy is designed to elicit an immune response against an individual’s tumor – a response analogous to an autoimmune disease where male sex is protective. We propose that regardless of sex, intratumoral androgens (sex hormones) suppress the anti-tumor immune response. Our goal is to unravel how sex hormones shape the immune cell landscape within a tumor, identify the source of sex hormone synthesis within a tumor, and target these pathways with small molecules to improve immune cell function.
Hormone receptor antagonism and checkpoint blockade
Prostate cancer is the second most common cancer in American men and the third leading cause of cancer associated death. While many forms of prostate cancer are highly responsive to therapy and lead to long-term survival, 1 out of 40 men will die from their disease. Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease with limited treatment options. Unlike in melanoma or lung cancer, immunotherapy has shown little efficacy in men with prostate cancer. However, in a recent clinical trial here at OHSU, when PD-1 blockade was combined with an androgen receptor antagonist (enzalutamide), there was an ~18% response rate. Our laboratory is interested in uncovering mechanisms of synergy between sex steroid antagonism and checkpoint blockade in patient and murine tumors. We have a strong collaboration with the Prostate Cancer Group and seek to improve therapy options for men with mCRPC.
Evaluating the impact of androgen deprivation therapy on T cell function
The standard of care treatment for advanced prostate cancer patients is androgen deprivation therapy. This treatment reduces circulating levels of testosterone by upwards of 90%, however, tissue levels of androgens and the production of adrenal androgens can promote androgen receptor signaling. We are exploiting standard of care treatment and clinical trials to directly evaluate how androgen deprivation therapy and androgen receptor targeted therapy could be modulating immunity in cancer patients. We work in partnership with oncologists and urological oncologists to obtain patient PBMCs and tumor biopsies for translational studies.