PROJECT SUMMARY
The treatment of cancer has been revolutionized by the development of immune-based therapies designed to
boost the number and function of cytotoxic T cells that kill tumor cells. However, it is already apparent that this
strategy alone will not benefit all patients, as the majority of cancers generate a highly immunosuppressive
tumor microenvironment (TME) that shuts down even the most potent T cells. Furthermore, as a consequence
of ramping up the immune system, these immune stimulating drugs instigate significant autoimmune toxicity.
This proposal aims to develop a radical new strategy to circumvent both challenges by identifying
immunosuppressive regulatory mechanisms unique to cancerous tissues, thereby uncovering pathways active
only in tumors that can be targeted to generate precision cancer immunotherapies that preserve immune
tolerance in healthy tissues. The focus will be on Regulatory T cells (Tregs), a subset of immunosuppressive
CD4+ T cells that lie at the fulcrum of immunity, directing cells of the immune system to go or stop. In cancer,
Tregs infiltrate tumors and dampen anti-tumor immune responses, but Tregs also play an essential role in
preventing autoimmunity. This proposal will test the hypothesis that human cancers generate an
immunosuppressive TME by enforcing a unique epigenetic program in intratumoral Tregs that, if identified, could
provide new targets to selectively modulate tumor-infiltrating Tregs and limit autoimmunity. To do this, the
research will employ genetically engineered mouse (GEM) cancers, an accurate and flexible platform to test
the full complement of factors that make up the TME of human cancers, combined with sophisticated genetic
tools to track Treg entry and activity in the TME to resolve: (1) how the native location wherein a cancer arises,
(2) how the underlying genetic drivers of cancer, and (3) how the immunogenicity of cancer, shape the
epigenetic state of intratumoral Tregs. The identification of epigenetic mechanisms controlling context-specific
adaptation of immune cell function in cancer would represent a major breakthrough not only for developing
precision cancer immunotherapies, but also for treating infectious diseases and autoimmunity with heightened
precision.