Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells

Area of Science:

• Immunology
• Oncology
• Cancer Metabolism

Background:

• Immunotherapy targeting the programmed cell death protein 1/PD-1 ligand (PD-1/PD-L1) pathway has transformed metastatic cancer treatment.
• PD-L1 is upregulated in solid tumors like lung cancer, particularly within lactate-rich tumor microenvironments.

Purpose of the Study:

• To investigate the role of lactate in inducing PD-L1 expression in lung cancer.
• To elucidate the molecular mechanisms linking lactate metabolism to PD-L1 upregulation and immune evasion.

Main Methods:

• Investigated PD-L1 induction by lactate in lung cancer cells.
• Utilized G-protein coupled receptor 81 (GPR81) silencing and lactate dehydrogenase A (LDHA) inhibition.
• Analyzed cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) activity, and transcriptional coactivator with PDZ-binding motif (TAZ) signaling.
• Assessed TAZ-TEAD interaction and PD-L1 promoter activity.
• Evaluated effects on interferon-gamma production and T-cell apoptosis in co-cultured Jurkat cells.

Main Results:

• Lactate directly induces PD-L1 expression in lung cancer cells through GPR81 signaling.
• GPR81 activation upregulates PD-L1 in a manner dependent on LDHA, mimicking in vivo glycolysis.
• The pathway involves decreased cAMP and PKA activity, leading to TAZ activation and subsequent PD-L1 transcription via TEAD.
• Lactate-induced PD-L1 reduces interferon-gamma and promotes Jurkat T-cell apoptosis.

Conclusions:

• Lactate plays a critical role in promoting tumor cell immune evasion by upregulating PD-L1.
• This study establishes a direct link between tumor metabolic reprogramming (glycolysis) and immune escape mechanisms.
• Targeting the lactate-GPR81-PD-L1 axis presents a potential therapeutic strategy for enhancing anti-tumor immunity.