Immune checkpoint Inhibitor-Induced Autoimmune Diabetes: Immunological Mechanisms and Biomarker Discovery in Provoked Beta Cell Autoimmunity

Project Summary/Abstract Within the last decade, immune checkpoint inhibitors (CPIs) have changed the landscape of cancer care, but also heightened risk for a range of endocrinopathies. While CPI treatment has led to tremendous benefits in a subset of cancers, they also have led to new-onset autoimmune disease (also known as “immune related adverse events” or “irAEs”) that can involve almost every organ. Within endocrine organs, insulin dependent autoimmune diabetes (CPI-DM) is highly morbid and potentially lethal. With this proposal Dr. Quandt plans a multipronged approach to address the mechanistic understandings of CPI-DM as examples of provoked autoimmunity. In Aim 1, Dr. Quandt will address genetic predisposition to CPI-DM. In Aim 2, Dr. Quandt will use an unbiased high throughput assay for novel autoantigen discovery to elucidate the specificity of the immune response in CPI-DM. In Aim 3, Dr. Quandt will use single cell methodologies to identify cellular phenotypes, activation, and differential gene expression contributing to a transcriptional signature critical to CPI-DM development. These studies will contribute to mechanistic understanding of CPI-DM with hope that they may lead to identification of actionable targets that could be used in the prevention or treatment of type 1 diabetes mellitus (T1DM), both in the setting of cancer immunotherapy and conventional disease. Dr. Quandt’s goal is to become a translational physician-scientist specializing in the immunology of T1DM and endocrine related aspects of cancer care, including endocrine irAEs. Bridging the divide between patient care and bench science is critical to furthering medical knowledge in both these novel and well-established autoimmune diseases. Dr. Quandt will advance her current experience in endocrinology, epidemiology and biostatistics through further training in wet lab approaches and bioinformatics including genetic analysis and computational immunology. This experience will anchor her understanding of translational methods to match her clinical research expertise. Her team of mentors, scientific advisors and collaborators are leaders in their respective fields. This training plan and scientific team will be coupled with the exceptional environment provided by the University of California, San Francisco, ensuring that Dr. Quandt will successfully advance to meet her career goal and transition to independence.