PROJECT SUMMARY (COLLABORATIVE PROJECT) Immune-related adverse events (IRAEs) are an emerging group of endocrine autoimmune diseases that occur in many patients treated with immune checkpoint inhibitor cancer therapy. IRAEs are an accelerated version of autoimmune endocrinopathy, and can affect the thyroid, pancreas, and pituitary glands, as well as numerous other tissues in the body. Understanding the drivers of rapid autoimmune progression in IRAEs can provide insight into mechanisms of human autoimmunity more broadly and identify potential therapeutic targets to slow or halt autoimmune responses. We recently reported increased effector conversion and clonal expansion of Tcf1+ progenitor T cells in patients with immune checkpoint inhibitor-thyroiditis and a mouse model of IRAEs. Furthermore, we showed that this effector conversion was driven by soluble factors from T follicular and T peripheral helper T cells, key components of tertiary lymphoid structures (TLS). Tcf1+ stem-like progenitor T cells play a key role in mediating effective immune responses in chronic viral infections and tumor immunity and colocalize to TLS. Thus, we hypothesize that increased conversion of Tcf1+ stem-like progenitor T cells, promoted by checkpoint inhibition and TLS factors, drive accelerated autoimmune responses in endocrine tissues in IRAEs. In Specific Aim 1, Dr. Lechner will investigate the changes in stem-like progenitor T cells over time in patients who develop IRAEs during checkpoint inhibitor compared to individuals with no autoimmunity, as well as controls with gradually progressing spontaneous autoimmune endocrinopathies. By simultaneously evaluating antigen-specific T cell function and expansion over time, Lechner will test the hypothesis that increased clonal expansion and conversion to effector function drive the development of rapid autoimmunity in IRAEs. In addition, spatial localization of immune cells within tissues impacts autoimmune disease progression. Co-localization of stem-like progenitor T cells within TLS and TLS-associated soluble factors provide potential targets to slow autoimmune responses. Thus, in Specific Aim 2, Dr. Lechner will delineate the spatial immune landscape within endocrine tissues from individuals with IRAEs, spontaneous autoimmunity, or no autoimmunity leveraging new techniques in spatial transcriptomics. These studies will test how cellular interactions and soluble factors within TLS contribute to clonal expansion and effector function of stem-like progenitor T cells during checkpoint inhibitor therapy and spontaneous autoimmune endocrinopathies. As a collaborative project amongst ACEs, these Aims and approaches can be extended to the evaluation of specimens from individuals with IRAEs and spontaneous autoimmunity in other organs, with the overarching goal of delineating temporal and spatial dynamics of stem-like progenitor T cells in human autoimmune disease. Furthermore, these studies can identify factors associated ...