Single-cell dissection of CD4 T cell changes in patients with immune-related adverse events following PD-1 inhibition

项目总结

Project Summary This application proposes a five-year research and training plan with a scientific focus on the mechanisms through which PD-1 checkpoint inhibition leads to immune-related adverse events (irAEs). The hypothesis is that de novo loss of PD-1 signaling enhances the antigen sensitivity of CD4 T cells and leads to the activation of autoreactive CD4 T cells that mediate irAE development. To investigate this hypothesis, the candidate will analyze two complementary human cohorts of his mentors: a) a prospective irAE cohort of patients on PD-1 immunotherapy to compare the early changes of CD4 T cells in patients who do (irAE+) and do not (irAE-) develop irAEs, and b) a cohort of patients on PD-1 immunotherapy that receive seasonal influenza vaccination to test whether any underlying immunopathology in irAE+ patients, not otherwise observed with evaluation of basal states, can be revealed with the help of immunization. Using the prospective irAE cohort, Aim 1 will evaluate whether patients that develop irAEs have a different naïve CD4 T cell epigenetic and transcriptional profile at baseline that allows robust activation of autoreactive CD4 T cells following PD-1 inhibition. Further, this aim will analyze the transcriptional profile and clonal diversity of the activated CD4 T cells generated after PD-1 inhibition in irAE+ patients. Using the aPD-1 cohort of influenza vaccination, Aim 2 will answer the question of whether PD-1 signaling is required to finetune the TCR threshold and transcriptional profile of CD4 T cell responses to maintain immune fitness and homeostasis. These studies will define the path through which PD-1 inhibition leads to the activation and propagation of autoreactive CD4 T cells to cause immune-mediated pathology. They will also identify cellular and molecular targets that can be used for early diagnosis and treatment of patients with rheumatologic and other irAEs. Scientifically, the candidate’s career development goals are to gain expertise in the conduct of clinical and translational research, bioinformatic analyses, single-cell technologies, and transcriptional and epigenetic regulation of autoimmune pathways in patient samples. Professionally, the candidate aims to gain experience in scientific writing, grant preparation, communication, and data presentation culminating to an R01 submission. To facilitate the candidate’s growth as a physician-scientist, this proposal combines novel experimental single-cell approaches and a specific career development plan designed by the candidate and his mentors, Dr. Wherry and Dr. Laufer. The candidate’s long-term goal is to transition to a tenure- track faculty position and to develop an independent NIH-funded research program focusing on the mechanisms of autoimmunity and T cell dysfunction to ultimately prevent and treat rheumatologic diseases. The rich scientific and collaborative environment at the University of Pennsylvania will position the candidate to have a highly impactful, translational research career in human autoimmunity.