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.
