Abstract 3415: Tumor fitness and immune exhaustion: Checkpoint vs endogenous settings

Abstract

Abstract Recently proposed tumor fitness measures based on neoepitope profiling and viral epitope similarity have led to treatment efficacy and immune response prediction models in the checkpoint setting for melanoma (SKCM) and small-cell lung cancer (NSCLC). In this work we test if these checkpoint based fitness measures are associated with either tumor-infiltrating T-cell activity or abundance, and also overall patient survival, in the endogenous setting for the SKCM (n=337) and NSCLC (n = 307) TCGA cohorts. We also investigated if epitopes arising from tumor viral co-factors in Hepatitis B liver cancer (HBV+ HCC) drove T cell activity or response compared to neo-epitope burden. We find no statistically significant correlation between immune activity and response (as measured by tumor RNA-seq profiling) and the proposed neo-epitope checkpoint-based fitness measures, and similarly no significant survival effect. Further, we found firm evidence that tumor neoepitopes dominate HBV viral epitopes in putative immunogenicity and drive immune response in TCGA HCC (n = 178), and confirmed this trend in multi-regional data (12 patients, 72 samples). These results suggest that tumor-immune response and recruitment in SKCM and NSCLC, and their interplay with viral-cofactor HBV in HCC, are fundamentally driven by different factors in the endogenous setting. Finally, we propose that tumor fitness may be partially encoded by a simple T-cell exhaustion expression signature, which we demonstrate is a significant predictor of patient survival for SKCM and NSCLC and may translate more widely into other tumor types in the endogenous setting. Citation Format: Adrian Bubie, Nicholas Akers, Augusto Villanueva, Bojan Losic. Tumor fitness and immune exhaustion: Checkpoint vs endogenous settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3415.