The project aims to investigate the immunological mechanisms that influence susceptibility to immune-related adverse events (irAEs) associated with immune checkpoint blockade (ICB) therapies. We have identified that the SNP rs7164391, located in a non-coding intronic region of the transcription factor gene RORA, is associated with an increased risk of irAEs in the PREMIS cohort. This strong statistical association has been successfully replicated in two independent cohorts: one from the Dana-Farber Cancer Institute and the other from the STING study at Gustave Roussy (Villejuif). RORA is a key regulator of CD4+ T cell polarization toward Th17 cells, which are involved in autoimmune immunopathological processes.
This project will leverage a combination of advanced genomic and functional approaches. The functional impact of the candidate variant rs7164391 on CD4+ T cell polarization will be assessed in vitro using prime editing, a method that introduces the nucleotide polymorphism to study transcriptomic differences at the single-cell level based on genotype. In parallel, single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients selected based on their rs7164391 genotype will provide important biological insights. The identification of expression quantitative trait loci (eQTLs) linked to this variant will further highlight its functional implications in shaping immune responses in ICB-treated patients.
The anticipated results will help uncover the genomic and immunological mechanisms associated with rs7164391 and its role in irAE development. Ultimately, this project will contribute significantly to advancing our understanding of the genetic predisposition to irAEs in patients receiving ICB therapy.
