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

• Published in: Journal of translational medicine 2023-07, Vol.21 (1), p.461-461, Article 461
• Main Authors: Gao, Chenggang, Chen, Jiaoshun, Bai, Jianwei, Zhang, Haoxiang, Tao, Yanyi, Wu, Shihong, Li, Hehe, Wu, Heshui, Shen, Qiang, Yin, Tao
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Antineoplastic Agents; Apoptosis; B7-H1 Antigen - genetics; Bioinformatics; Care and treatment; CD8 antigen; CD8-Positive T-Lymphocytes; Cell death; Cells; Complications and side effects; Cytotoxicity; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental; Down-regulation; Down-Regulation - genetics; Epidermal growth factor; Epidermal growth factor receptors; Flow cytometry; Glucose; Glucose metabolism; Glucose tolerance; Health aspects; Immunoprecipitation; Immunosuppression; Intolerance; Lymphocytes; Lymphocytes T; Medical prognosis; Mice; Mice, Inbred C57BL; mRNA stability; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; PD-L1; PD-L1 protein; Peptidyl-tRNA hydrolase; Prevention; Proteins; Risk factors; RNA binding protein; Signal Transduction; Transfer RNA; tRNA; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04302-4

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. 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. 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. 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.