High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment

• DOI: 10.1186/s12967-023-04302-4
• Publication Date: 2023-07-11T18:02:21Z
• Authors: Chenggang Gao; Jiaoshun Chen; Jianwei Bai; Haoxiang Zhang; Yanyi Tao; Shihong Wu; Hehe Li; Heshui Wu; Qiang Shen; Tao Yin
• Keywords: PD-L1; Research; Diabetes; R; Down-Regulation; Antineoplastic Agents; CD8-Positive T-Lymphocytes; RNA binding protein; B7-H1 Antigen; 3. Good health; Diabetes Mellitus, Experimental; Pancreatic ductal adenocarcinoma; Mice, Inbred C57BL; Pancreatic Neoplasms; Mice; Tumor microenvironment; Tumor Microenvironment; Medicine; Animals; Signal Transduction

Abstract 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.