Dissecting auto-reactive and tumor-specific T cells in tumor patients undergoing immune checkpoint inhibitor treatment and suffering from immune-related adverse events

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Checkpoint inhibitor-based immunotherapies (ICI) show remarkable efficacy in various tumor entities, but are also associated with significant immune-related adverse events (irAE) leading to increase of morbidity and therapy discontinuation or even being fatal in the worst case. Nevertheless, pathomechanisms of these ICI-induced adverse effects have so far insufficiently investigated and most mechanistic assumptions and hypotheses are based on known mechanisms of action against tumors. Given the widespread PD1 expression among immune cell populations, we hypothesized that capturing quantitative and functional changes in circulating leukocyte populations in the blood might provide new insights regarding the causes and driving mechanisms of irAE in ICI-treated cancer patients. Thus, we conducted a longitudinal whole blood screening study in patients undergoing anti-PD1 antibody treatment.A major finding of this exploratory study was a marked increase in distinct activated T cell populations, which was often observed before diagnosis of irAEs.Assuming that the activated effector T cells, which were significantly elevated in irAE patients, are partially autoaggressive (non-malignant tissue-specific), we now plan to perform simultaneous studies on transcriptome and TCR clonality by scRNAseq in addition to their longitudinal quantification (dynamics in the clinical course). Further linkage with TCR bulk sequencing of sorted T cell subpopulations will allow us to trace the differentiation pathway and populations of origin of potential pathogenically autoreactive and therapeutic T cells. Second, using the TCR sequences of expanded TCR clones and prediction algorithms, candidate peptides will be identified and validated in co-culture experiments including T cell function analyses to assess their antigen specificity. Comparison of the T cell transcriptomes of identified tumor-specific and auto-reactive T cells will determine therapeutically-relevant differences, as well as identify different tissue-related signaling/immune/inflammatory patterns depending on the different irAE-affected tissues.The combination of these studies has the potential to reveal characteristic differences between tumor-specific, auto-aggressive, and unrelated activated bystander T cells and to provide a basis for the development of flexible and adjustable ICI therapies. In doing so, the project outlined aims to elucidate novel pathomechanisms that are critical to the development and progression of irAEs. Furthermore, insights into how PD1 controls autoimmune processes in humans and the role of T cells during the early phase of autoimmune diseases could be gained.