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

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.

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

“…In future studies, the relationship between metabolic reprogramming and tumor immune escape should be fully considered to optimize therapy and avoid problems, such as off-target immunity, drug resistance, and possible metastasis, and the ineffectiveness of targeted metabolic therapy. The targeting of glucose metabolism and glutamine metabolism may directly regulate the expression of PD-L1 in tumor cells ( 36 , 61 ), which modulate the effects of targeted metabolic therapy because it may cause tumor immune escape. Therefore, the combined use of targeted glucose or glutamine metabolic therapy and PD-L1 ICIs may induce a synergistic effect.…”

“…PD-L1 is a negative immunoregulator that is regulated by glycolysis in many tumors. In vitro experiments found that a reduction in glucose content in the culture medium upregulated the expression of PD-L1 in renal cancer cells via the EGFR/ERK/C-Jun pathway ( 36 ). The expression of PD-L1 correlated with the uptake of 18 F-FDG in lung adenocarcinoma ( 37 ).…”

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

“…Apart from this, PD-L1 and glycolysis have been shown to be positively correlated, although it is currently unclear whether PD-L1 expression enhances glycolysis or vice versa. One study has shown that glucose deprivation lead to an up-regulation of PD-L1, while siRNA knockdown of PD-L1 likewise decreased expression of glycolysis enzymes (specifically PFKFB3) in NSCLC cell lines ( 95 ). Further, another investigation found that PD-L1 increased expression of the glycolysis enzyme HK2 in SCC NSCLC ( 96 ).…”

“…Further, another investigation found that PD-L1 increased expression of the glycolysis enzyme HK2 in SCC NSCLC ( 96 ). These studies suggest that PD-L1 may be directly involved in the up-regulation of glycolysis and elude to potential signaling mechanisms such as PI1K/AKT/mTOR, EGFR, and HIF-1α ( 95 – 98 ). Interestingly, other investigations have concluded that the metabolic switch towards glycolysis is essential for PD-L1 overexpression ( 99 , 100 ).…”

PD‐1/PD‐L1 inhibitors‐based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies

“…Glucose deficiency could reduce the energy produced by glycolysis pathway and promote downstream ERK/c‐Jun phosphorylation by activating EGFR, thereby enhancing PD‐L1 expression. 90 In high‐grade RCC, glucose‐converted glutamine is used to alleviate oxidative stress via the glutathione pathway, and the grade of RCC was positively correlated with the expression of glutamine depletion signature. 91 , 92 Glutamine deprivation has been demonstrated to induce PD‐L1 expression by stimulating the EGFR/ERK/c‐Jun signaling pathway.…”