Assessment of germline variants associated with immune-related adverse events following immune checkpoint inhibitors

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but come with the significant downside of immune-related adverse events (irAEs), which can lead to treatment discontinuation, hospitalization, or even death. Understanding the mechanisms behind irAEs is imperative, not only to minimize toxicity but also because irAEs are paradoxically linked to positive anti-tumor responses, while their aggressive management correlates with increased relapse risk. Our research posits that gaining a nuanced understanding of the biological mechanisms underlying irAEs could enable clinicians to differentiate between clinical benefits and harmful side effects, thus optimizing immunotherapy efficacy. We have previously shown that germline variants are associated with irAEs, and have also noted that somatic alterations impact immunotherapy efficacy by interacting with the immune environment. Short-term Objectives: Aim 1: We plan to conduct the largest genome-wide association study (GWAS) for irAEs, covering over 13,000 ICI patients, using novel imputation and survival models. This will include aggregating pan-cancer data across multiple cohorts. We aim to characterize shared and distinct genetic architectures of irAE subtypes and evaluate how germline variants interact with therapy agents to influence safety and efficacy outcomes. We will aggregate germline data for 13,000 patients to conduct a GWAS for irAEs and clinically annotate and aggregate pan-cancer data. Sub-population GWAS will identify subtype/organ-specific germline associations. Longitudinal competing event models will be used to assess the mechanistic effects of each variant on safety and efficacy outcomes. Aim 2: We will delve into the cell-type-specific mechanisms, tumor microenvironment interactions, and ancestral variability of germline irAE variants. Bulk and single-cell RNA-seq (sc-RNA-seq) data will be integrated to elucidate these mechanisms, and somatic alteration interactions will also be analyzed. RNA-seq and tumor/blood scRNA-seq will be utilized to identify cell-type-specific mechanisms and interactions of germline variants with somatic drivers. Long-term Objectives: Our long-term goal is to personalize immunotherapy by tailoring it to individual genetic makeup, thus minimizing irAEs and optimizing efficacy. This could dramatically improve cancer treatment outcomes and reduce healthcare burdens associated with complications, contributing to public health. By dissecting the genetic landscape and its interaction with immunological and somatic factors, our work aims to pave the way for safer and more effective cancer immunotherapies.