Journal of Translational Medicine
Background: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. Methods: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells. Results: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice. Conclusions: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Gao, Chenggang; Chen, Jiaoshun; Bai, Jianwei; Zhang, Haoxiang; Tao, Yanyi; Wu, Shihong; Li, Hehe; Wu, Heshui; Shen, Qiang; and Yin, Tao, "High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment" (2023). School of Graduate Studies Faculty Publications. 114.
Amino Acids, Peptides, and Proteins Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Chemical Actions and Uses Commons, Neoplasms Commons, Nutritional and Metabolic Diseases Commons, Oncology Commons