NIH Reporter #5K08AR081929-04

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

A five-year NIH-funded research project studying how PD-1 inhibition causes immune-related adverse events by activating autoreactive CD4 T cells, aiming to identify targets for diagnosis and treatment.

Description

This application proposes a five-year research and training plan focusing 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, activating autoreactive CD4 T cells that mediate irAE development. The study involves analyzing human cohorts to compare early changes in CD4 T cells and their transcriptional and epigenetic profiles, as well as their clonal diversity, to understand how PD-1 inhibition activates autoreactive T cells and causes immune-mediated pathology. The research aims to identify cellular and molecular targets for early diagnosis and treatment of irAEs, with a long-term goal of developing an NIH-funded research program on autoimmunity and T cell dysfunction.

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