Discovering and characterizing the germline mechanisms of cutaneous immune-related adverse events (cirAE)

Project Summary Immune checkpoint inhibitors (ICIs) have revolutionized advanced cancer care, with up to 44% of all cancer patients eligible for ICI therapy as of 2019, representing 230,000 patients annually in the US alone. However, ICIs are associated with morbid and potentially fatal toxicities, known as immune-related adverse events (irAEs). In this work, we propose to study the genetic landscape of cutaneous irAEs (cirAEs) by analyzing germline data from thousands of ICI recipients and integrating with carefully collected spatial and longitudinal molecular data across multiple scales. No germline association studies of cirAEs have been performed to date, with an urgent need for discovery and functional follow-up. First, we will identify germline variants associated with cirAEs across >10,000 immunotherapy patients. We will investigate the genetic mechanisms of common germline variants; common and rare HLA alleles; as well as germline interactions with tumor and/or environmental features. Second, we will characterize the causal genes and phenotypic consequence of cirAE-associated variants. We will integrate population-scale RNA-seq data to identify the causal genes mediating cirAE events; we will investigate the downstream effects on anti-tumor response and overall survival; and we will identify associations with extremely severe cirAEs. Third, we will carry out prospective molecular phenotyping to map the precise mechanisms of cirAE risk in time and space for genotyped patients with skin cancer. For patients on ICIs, we will prospectively collect tissue for spatial profiling, TCR sequencing, and proteomics to comprehensively assay the precursors and consequences of cirAEs. If successful, our proposal will increase our understanding of the genetic architecture of cirAEs, identify avenues for therapeutic intervention and patient stratification to mitigate irAEs across organ systems, and potentially identify new ways of heightening the broader anti-tumor effect of ICIs.