Mechanisms of Checkpoint Receptor Inhibitor-dependent Immune-related Adverse Events

Dr. Damo is particularly interested in immune related adverse effects (irAEs,) side-effects that can happen with the use of checkpoint receptor inhibitors (CPI) in immunotherapy targeting cancer.  The development of checkpoint receptors has resulted in a paradigm shift in cancer immunotherapy, significantly improving the clinical outcome and life expectancy of many patients across different types of cancer, but up to 80% of patients experienced irAEs, localized autoimmunity issues where the immune system attacks the body, most often on the skin or in the gastrointestinal track. Dr. Damo has developed a new mouse model that allows her to reproduce human irAEs on mouse skin, which has demonstrated that checkpoint receptors like PD-1 play a key role in preventing T cells from attacking healthy skin cells and that once checkpoint receptors are inhibited, T cells tend to destroy those cells creating an irAE-like disease.

With her CRF Young Investigator Award, Dr. Damo will build on this finding, testing her hypothesis that T cells specific for antigens expressed in healthy tissues can infiltrate these tissues and remain tolerant via checkpoint  receptor-mediated regulation. Checkpoint inhibitor immunotherapy then causes irAEs by functionally unleashing these T cells that have infiltrated the healthy tissue and making them intolerant. She plans to study the underlying mechanisms and the translational consequences of this hypothesis by delving into the mechanisms of checkpoint receptor-dependent T cell tolerance in skin and comparing skin-specific T cell responses and tumor-specific T cell responses in the context of CPI immunotherapy. These studies will contribute to our understanding of the development of skin irAEs, and they will provide an experimental blueprint for future development of her innovative “NINJA”-based mouse models of tolerance and irAEs in other organs. Dr. Damo hopes to continue to refine her model to further understanding of the physiology of checkpoint receptors, of why the therapeutic blockade of checkpoint receptors can be toxic, and to discover druggable targets that can mitigate irAEs by curtailing the anti-tissue effects of CPIs without affecting their anti-tumor effects.