Pilot Project 2: Comprehensive characterization of Immune Features Linked to Genetic Variants and Response to Immunotherapy

Project Summary Lung cancer is a leading cause of cancer death in the U.S. Although many actionable biomarkers and targeted treatments can significantly prolong lung cancer survival, some patients remain less likely to receive next-generation sequencing testing than others. Our preliminary analyses on real-world, observational data of clinical tumor sequencing show that environmental and genomic markers may influence lung cancer mutation profiles, in particular the effect of smoking exposure on developing KRAS-mutant lung cancer. Moreover, there is a significant enrichment of high tumor mutation burden, which is a biomarker for immune checkpoint inhibitors, independent of smoking status. In this project, we will identify germline variants or environmental/social factors influencing the tumor genome of lung cancers. We will also assess the joint effect of genetic variability and smoking, on somatic mutations and tumor-immune features. We will perform immune profiling on immunotherapy-treated patients. We will assess the inflammatory mediators from plasma samples of patients to understand how different factors in innate immunity may impact patients’ immunotherapy outcome. The proposed study will broaden our knowledge about the complex relationship between genomic variation, environmental exposure and immune interaction contribute to tumor genomic differences. The findings will improve lung cancer diagnostic testing and immunotherapy outcome prediction, and lead to the discovery of new treatment options for cancer patients. In this proposal, we will identify and characterize somatic biomarkers in tumors, stratified by genetic variability markers. These studies will improve clinical genomic testing and uncover therapeutic targets.