Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

Abstract

Recently proposed tumor fitness measures, based on profiling neoepitopes for reactive viral epitope similarity, have led to improved prediction models of response to immune checkpoint inhibitors in melanoma and small-cell lung cancer.Here we apply these checkpoint based fitness measures in the matched checkpoint-treatment naive TCGA samples where cytolytic activity imparts a known survival benefit. No significant survival predictive power beyond that of overall patient tumor mutational burden is observed in either cohort, and furthermore, there is no observed association between checkpoint based fitness and tumor T-cell infiltration, cytolytic activity (CYT), or abundance (TIL burden).We investigate the key assumption of viral epitope similarity driving immune response in the hepatitis B virally infected liver cancer TCGA cohort, and uncover suggestive evidence that tumor neoepitopes dominate viral epitopes in putative immunogenicity and plausibly drive immune response.Significance: Tumor fitness does not predict patient survival better than tumor mutation burden, unlike a measure of CYT. In checkpoint treatment naive patients, our results suggest TIL recruitment and cytolytic activity are essentially driven by tumor neoepitopes, regardless of the presence of viral epitopes.