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

编号：

b0824d21-7c10-4706-84bc-682cd61b7597
作者：

Feng, J.(凤景)#^[1]Yang, H.#^[2]Zhang, Y.(章尧)^[3]Wei, H.^[4];Zhu, Z.^[5,6];Zhu, B.;Yang, M.#^[7]Cao, W.#^[7]Wang, L.*^[1,8]Wu, Z.(吴志浩)*^[3,8]
语种：

英文
期刊：

ONCOGENE ISSN：0950-9232 2017 年 36 卷 42 期 (5829 - 5839) ; OCT 19
收录：
摘要：

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-gamma 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.
推荐引用方式
GB/T 7714：

Feng J.,Yang H.,Zhang Y., et al. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells [J].ONCOGENE,2017,36(42):5829-5839.
APA：

Feng J.,Yang H.,Zhang Y.,Wei H.,&Wu Z..(2017).Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells .ONCOGENE,36(42):5829-5839.
MLA：

Feng J., et al. "Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells" .ONCOGENE 36,42(2017):5829-5839.
入库时间：

10/2/2017 12:00:00 AM
更新时间：

10/2/2017 12:00:00 AM

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