Background: Pancreatic adenocarcinoma (PDAC) is an extremely immunosuppressive and heterogenous neoplasm for which immune checkpoint inhibitor therapy has not been very successful. 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 also influence the extracellular matrix in the tumor microenvironment. Our study aims to sensitize pancreatic cancer to anti PD-1 therapy by targeting the HBP pathway.
Methods: 6-Diazo-5-oxo L-norleucine or DON was used as a GFAT inhibitor. Tetracycline-inducible GFAT knockout cell lines were made using S2-VP10 as the parent cell line.
Results: High-dose monotherapy of DON (1mg/kg/3days a week) caused significant decrease in tumor volume in immunocompetent KPC mice along with significant reduction in metastasis and circulating tumor cells. Circulating tumor cells (CTCs) were also found to be significantly reduced in DON-treated mice as compared to control, leading to reduced metastasis. Combination of low-dose DON (0.5mg/kg/3 days a week) with low-dose anti PD-1 (100 μgX3 times) caused an impressive reduction in tumor volume along with an increase in survival in KPC tumor-bearing mice. Flow-based analysis of tumor cells show a significant influx of CD8+ T cells along with an increase in M1 polarization of macrophages. Survival study of CD8 knockout mice (CD8KO), orthotopically implanted with KPC and fibroblast cells, show that at low doses DON loses its anticancer effect in absence of CD8 as demonstrated by decrease in survival in CD8KO mice as compared to tumor-bearing wild-type mice.
Conclusion: Novel therapeutic strategies that can make PDAC more amenable to immune therapy are urgently needed. In this context, our study is extremely timely as it targets specific metabolic pathways in cancer cells to overcome immune resistance and sensitize the tumor to anti-PD1 therapy.
Citation Format: Nikita S. Sharma, Vineet K. Gupta, Vanessa Garrido, Roey Hadad, Brittany Durden, Kousik Kesh, Anthony Ferrantella, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Targeting tumor-intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix, and sensitizes to anti-PD1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B03.