Targeting tumor intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix and sensitizes to anti-PD1 therapy.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA-4, PD-1, PD-L1) has not been very successful against PDAC.\n\nThe robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize UDP-GlcNAc.\n\nIn the current manuscript, we target this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-L-norleucine or DON). Our results show that DON decreases the self-renewal potential and metastatic ability of tumor cell. Further, treatment with DON results in a decrease in hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM. this in turn, increases CD8+ cytotoxic T-cells infiltration, and makes the tumors tumors more amenable and sensitive to anti-PD1 therapy.