Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

• DOI: 10.1172/jci127515
• Publication Date: 2019-10-15T17:04:28Z
• Authors: Nikita S. Sharma; Vineet K. Gupta; Vanessa T. Garrido; Roey Hadad; Brittany C. Durden; Kousik Kesh; Bhuwan Giri; Anthony Ferrantella; Vikas Dudeja; Ashok Saluja; Sulagna Banerjee
• Keywords: Pancreatic tumor

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of tumor better understanding microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that rich in hyaluronan, plays integral role this evasion. Hexosamine biosynthesis pathway (HBP), shunt glycolysis, metabolic node cancer cells can promote survival pathways on one hand influence hyaluronan synthesis ECM other. rate-limiting enzyme pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine fructose 6-phosphate eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In current manuscript, we targeted glutamine-utilizing by small molecule analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed DON decreased self-renewal potential metastatic ability cells. Further, treatment collagen leading remodeling increased infiltration CD8+ T Additionally, sensitized pancreatic tumors anti-PD1 therapy, resulting regression prolonged survival.