Abstract
Abstract Background: Pancreatic cancer is notoriously difficult to treat owing to its late detection, metastasis and increased therapeutic resistance, leading to a 5-year survival rate of 9%. Immune evasive microenvironment further contributes to challenges in developing viable therapy options. As a result, anti-PD-1 therapy that has shown promising results in various cancers like melanoma, non-small cell lung cancer and kidney cancer is ineffective against pancreatic cancer patients. Hexosamine biosynthesis pathway (HBP), a glutamine-dependent metabolic shunt pathway responsible for producing UDP-GlcNAc and thus glycosylation, is overexpressed in pancreatic cancer. Our study shows that targeting HBP by a glutamine analog DON in pancreatic cancer can sensitize it to anti-PD1 immune therapy. Methods: All experiments were done using primary cells isolated from spontaneous pancreatic cancer mice, KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (KPC), which are the epithelial cancer cells and the cancer-associated fibroblasts (CAFs) isolated from the same mice. 6-Diazo-5-oxo-L-norleucine (DON) was used as an inhibitor of GFAT, the rate-limiting enzyme of HBP. DON was used at a dose of 1mg/kg alone or 0.5mg/kg in combination with PD1 (100 microgm). Results: Our study showed mice orthotopically implanted with KPC and CAF cells at a ratio of 1:9 showed a marked decrease in tumor volume when treated with DON. In addition to a decrease in tumor volume, these mice also had a profound decrease in their circulating tumor cells and a significant reduction in the collagen content in the tumor while the stromal content remained unaffected. Mice treated with low-dose DON in combination with low-dose anti-PD1 therapy showed a pronounced decrease in tumor volume as compared to either treatments alone. As expected, mice treated with the DON+PD1 combination had an increased infiltration of CD4 and CD8 cells. Conclusion: Our study highlights for the first time an impressive response to PD1 therapy in pancreatic cancer when given in combination with DON, a glutamine analog. Since PDL1 depends on the HBP pathway for its glycosylation, inhibition by DON and the subsequent internalization of PDL1 leads to an increased immune response against pancreatic cancer that can be targeted therapeutically. Note: This abstract was not presented at the conference. Citation Format: Nikita S. Sharma, Vineet K. Gupta, Roey Hadad, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok K. Saluja, Sulagna Banerjee. Targeting the glutamine dependent hexosamine biosynthesis pathway sensitizes pancreatic tumors to anti-PD1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A59.