Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

作者：Haijing Deng, Anna Kan, Ning Lyu, Meng He, Xin Huang, Shuang Qiao, Shaolong Li, Wenhua Lu, Qiankun Xie, Huiming Chen, Jinfa Lai, Qifeng Chen, Xiongying Jiang, Shousheng Liu, Zhenfeng Zhang, Ming Zhao · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2021 · DOI：10.1136/jitc-2020-002305 · 被引用次数：176 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Chemokine receptors and signaling

Background Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1 + ) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1 + neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1 + neutrophils in hepatocellular carcinoma. Methods Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1 + neutrophil infiltration. Further in vivo assays were used for verification. Results Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1 + neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/ST...