2. Academic Validation
  3. Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment

Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment

  • Cell Death Discov. 2021 Jan 18;7(1):15. doi: 10.1038/s41420-021-00401-7.
Yongbo Yu  # 1 2,  Ye Liang  # 2,  Dan Li 2,  Liping Wang 2,  Zhijuan Liang 2,  Yuanbin Chen 2,  Guofeng Ma 1 2,  Hui Wu 1 2,  Wei Jiao 3,  Haitao Niu 4 5
Affiliations

Affiliations

  • 1 Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
  • 2 Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
  • 3 Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. [email protected].
  • 4 Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. [email protected].
  • 5 Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. [email protected].
  • # Contributed equally.
PMID: 33462221 DOI: 10.1038/s41420-021-00401-7
Abstract

Programmed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal Cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal Cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.

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