Regulatory T cell stability and plasticity in the tumor microenvironment
There are a number of subsets of CD4 T cells in both mouse and human. CD4+Foxp3+ T cells are known as regulatory T cells (Tregs) and are a unique subset of CD4 T cells whose function is to restrain immune responses rather than promote them. In the tumor microenvironment, regulatory T cells can contribute to the total immune suppression thereby limiting effective adaptive immune responses. Multiple approaches are underway to deplete regulatory T cells from the tumor microenvironment in order to enhance anti-tumor T cell responses. Another approach that our laboratory is taking is to identify mechanisms by which to transiently reprogram Tregs to become effector cells thereby enhancing the anti-tumor/anti-tissue T cell response.
Mechanisms of action of agonist and checkpoint inhibitors
T cell activation and dysfunction are active processes that require the ligation of stimulatory and inhibitory receptors on the cell's surface. In particular, chronic stimulation of a T cell through its T cell receptor leads to the upregulation of a number of inhibitory molecules including CTLA4 and PD-1. Using monoclonal antibodies to block these receptor-ligand interactions has demonstrated clinical success that is unparalleled by other therapies available to date. However, for each of these immune-based therapies, there is only a subset of patients that will achieve a clinical benefit. Combining multiple immunotherapy molecules is efficacious, and dissecting the mechanisms of synergy is an ongoing project in the laboratory.
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.