Abstract: This K08 proposal will expedite the principal investigator’s progress towards her goal of becoming an independent physician-scientist with a focus on increasing our understanding of mechanisms of immune related adverse events (irAEs) induced by checkpoint inhibitor (CPI) immunotherapies and identifying therapeutic targets of these complications. Candidate: Dr. Ana Perdigoto is a physician-scientist at Yale University School of Medicine. She completed clinical fellowship in Endocrinology and postdoctoral training in Immunology. She is developing an expertise at the crossroads of immuno-endocrinology and immuno- oncology through her work on investigating mechanisms of CPI-induced diabetes (CPI-DM), a complication that arises in cancer patients treated with immunotherapies targeting checkpoint inhibitors. Under the mentorship of Dr. Kevan Herold, a world-renowned Endocrinologist and Immunologist with authority on the immunology of type 1 diabetes and CPI-DM, Dr. Perdigoto investigated how immune cells modify pancreatic islets to cause CPI-DM. She will leverage the skills gained during her training to further analyze mechanisms of these irAEs. Career Development Plan: Dr. Perdigoto will pursue the research in this proposal under the primary mentorship of Dr. Herold. She will also have the guidance of an intramural and extramural advisory team with various areas of expertise and experience in nurturing independent investigators. Yale University provides a collaborative environment with state-of-the-art facilities and resources and excellent training environment and opportunities. The proposed 5-year plan builds on Dr. Perdigoto’s prior experience and further enriches her training to provide the tools needed for establishing independence, such as proficiency in bioinformatics and analysis of genomic data, knowledge in mouse genetics, and productive collaborations. Research Plan: The overall premises addressed in this proposal are that interactions of immune and islet cells in the tissue microenvironment lead to the development of CPI-DM (investigated in Specific Aim 1) and that tumor can impact autoimmunity, potentially through presentation of shared antigens (investigated in Specific Aim 2). Upon completion of the research proposed, Dr. Perdigoto will be able to: 1) characterize immune-target cell interactions that lead to autoimmunity 2) analyze novel tumor models with regards to the impact of immunotherapies and tumor on autoimmunity and 3) identify potential therapeutic targets to prevent adverse events without impacting tumor responses. The findings will enhance our understanding of the pathogenesis of CPI-DM as well as other irAEs arising from CPI treatment. After completing the proposed training, Dr. Perdigoto will have acquired the expertise required to become an independent investigator poised to continue translational studies that can lead to the development of diagnostic or therapeutic tools to protect target cells from the effects...