Metabolic alterations regulate
cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal
adenocarcinoma (PDAC) to conventional
immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic
enzyme screen indicated that elevated expression of CD73, an
ecto-5'-nucleotidase that generates
adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial
adenosine levels in
tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo
tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput
cytokine profiling demonstrated decreased
GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4+ and CD8+ T cells in pancreatic
tumors with CD73 knockdowns. Depletion of CD4+ T cells, but not CD8+ T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown
tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing
GM-CSF restored
tumor growth in Nt5e knockout
tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved
gemcitabine efficacy in orthotopic models. Thus, targeting the
adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC.