Association of heightened host and tumor immunity with prolonged duration of response to checkpoint inhibition across solid tumors

Abstract

Cancer immunotherapy is a beneficial therapy for many cancer types, but predictive pan-tumor biomarkers for clinical benefit are suboptimal. Our study, employing DNA and RNA based analysis, investigated the role of predicted neoantigens in the benefits of immunotherapy within a cohort of 88 patients of European descent with advanced solid tumors. Patients who had a prolonged (> 12 months) duration of immunotherapy exhibited heightened immune responses, characterized by increased levels of predicted neoantigens with strong HLA binding potential, elevated cytotoxic marker levels, and enhanced T cell activity. Furthermore, our analysis revealed associations between prolonged duration of therapy and rare variants, notably within the EPHA8 gene. These variants, exclusive to patients with a prolonged (> 12 months) duration of immunotherapy, suggest potential implications for immunotherapy response. In addition, the evolutionary conservation of these variants across vertebrate species underscores their functional importance in tumor biology and ultimately, treatment outcomes. Despite limitations in sample size and patient homogeneity, our findings emphasize the potential utility of understanding the molecular and immunological mechanisms underlying immunotherapy responses to further refine personalized treatment strategies.