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Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells
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Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells
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Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells
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Journal Article
Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells
2017
Overview
The clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein 1/PD-1 ligand (PD-1/PD-L1) has initiated a new era in the treatment of metastatic cancer. PD-L1 expression is upregulated in many solid tumors including lung cancer and functions predominantly in lactate-enriched tumor microenvironments. Here, we provided evidence for PD-L1 induction in response to lactate stimulation in lung cancer cells. Lactate-induced PD-L1 induction was mediated by its receptor GPR81. The silencing of GPR81 signaling in lung cancer cells resulted in a decrease in PD-L1 protein levels and functional inactivation of PD-L1 promoter activity. In addition, GPR81-mediated upregulation of PD-L1 in glucose-stimulated lung cancer cells that recapitulates the enhanced glycolysis
in vivo
was dependent on lactate dehydrogenase A (LDHA). We also demonstrated that activation of GPR81 decreases intracellular cAMP levels and inhibits protein kinase A (PKA) activity, leading to activation of the transcriptional coactivator TAZ. Interaction of TAZ with the transcription factor TEAD was essential for TAZ activation of PD-L1 and induction of its expression. Furthermore, we found that lactate-induced activation of PD-L1 in tumor cells led to reduced production of interferon-γ and induction of apoptosis of cocultured Jurkat T-cell leukemia cells. Our findings reveal an unexpected role of lactate in contributing to tumor cell protection from cytotoxic T-cell targeting and establishes a direct connection between tumor cell metabolic reprograming and tumor evasion from the immune response.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
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/ 13/2
/ 13/31
/ 13/95
/ 14/34
/ 38/22
/ 38/23
/ 38/77
/ 82/80
/ Cyclic AMP-Dependent Protein Kinases - genetics
/ Cyclic AMP-Dependent Protein Kinases - metabolism
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Interferon-gamma - metabolism
/ Intracellular Signaling Peptides and Proteins - genetics
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Kinases
/ Lactate Dehydrogenases - genetics
/ Lactate Dehydrogenases - metabolism
/ Medicine
/ Oncology
/ Proteins
/ Receptors, G-Protein-Coupled - genetics
/ Receptors, G-Protein-Coupled - metabolism
/ T cells
