CD73 is associated with glycolysis related metabolic programs and CD8+ T cell suppression in pancreatic ductal adenocarcinoma

Abstract

CD73 is an enzyme that generates extracellular adenosine and has been implicated in tumor-associated immune suppression, but its biological and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. We investigated the prognostic relevance and biological functions of CD73 in PDAC using transcriptomic analyses, in vitro functional assays, and in vivo mouse models. Transcriptomic analyses consistently showed that CD73 expression was correlated with hypoxia, glycolysis related, and cell-cycle programs. In agreement with these findings, hypoxic exposure induced CD73 mRNA expression in a subset of PDAC cell lines, and CD73 knockdown modestly affected glycolysis related extracellular acidification (ECAR) in a cell line dependent manner, and modulation of CD73 expression altered PDAC cell growth. CD73 expression was also associated with reduced intratumoral CD8+ T cell infiltration and cytolytic activity in human PDAC cohorts. In vivo, CD73 overexpression accelerated cancer progression and shortened survival in immunocompetent mice, whereas this effect was abrogated in immunodeficient NSG mice. Flow cytometric analysis further demonstrated reduced intratumoral CD8+ T cell infiltration in CD73 overexpressing tumors. Clinically, high CD73 expression was consistently associated with worse survival in multiple PDAC cohorts. Collectively, these findings suggest that CD73 is associated with multiple features of PDAC progression, including hypoxia-related metabolic programs, tumor growth, and suppression of anti-tumor immunity. CD73 may therefore represent a biologically relevant biomarker and a potential therapeutic target in PDAC.