Project Summary Lung cancer is the leading cause of cancer death among the African American population. Although many actionable biomarkers and targeted treatments are available to significantly prolong lung cancer survival, patients of non-European ancestry are less likely to undergo next-generation sequencing testing than their white counterparts. Our preliminary analysis based on real-world, observational data of clinical tumor sequencing show that although patients with African ancestry are enriched in tobacco smoking-induced mutational processes, there is an enrichment of TP53 and depletion of KRAS mutations, suggesting that African ancestry may modify 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 ancestry or race-specific environmental/social factors influencing the tumor genome of lung cancers. We will also assess the joint effect of African ancestry and smoking, on somatic mutations and tumor-immune features. We will perform immune profiling on immunotherapy -treated patients of African ancestry. We will assess the inflammatory mediators from plasma samples of patients of African ancestry and understand how different factors in innate response may impact patient’s immunotherapy outcome. The proposed study will broaden our knowledge about the complex relationship between genetic ancestry, environmental exposure and immune interaction contributing to genomic differences. The findings will improve lung cancer diagnostic testing and immunotherapy outcome prediction, and lead to future study and discovery of new treatment options for African American patients. Relevance. There is a significant racial disparity in lung cancer. In this proposal, we will identify and characterize somatic biomarkers in tumors from patients of African ancestry. These studies will improve clinical genomic testing and uncover therapeutic targets for this patient population.