CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis

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-gamma 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.

Automated summary

Metabolic alterations play a crucial role in regulating cancer aggressiveness and immune responses. This study found that elevated expression of CD73, an enzyme involved in generating adenosine, is associated with increased aggressiveness in pancreatic ductal adenocarcinoma (PDAC). Inhibiting CD73 expression led to reduced tumor growth and myeloid-derived suppressor cells (MDSC) in PDAC mouse models. Furthermore, CD73 knockdown resulted in increased IFN-gamma expression by intratumoral CD4(+) and CD8(+) T cells and decreased GM-CSF levels. Depletion of CD4(+) T cells, but not CD8(+) T cells, abolished the beneficial effects of CD73 reduction. Overall, targeting the adenosine axis presents a promising therapeutic strategy for enhancing the immune response against PDAC.