Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma.
Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma.
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肿瘤源性乳酸通过调节肝细胞癌中性粒细胞的PD-L1表达抑制乐伐替尼的疗效
DOI：
10.1136/jitc-2020-002305
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发表时间：
2021-06
影响因子：
10.9
通讯作者：
Zhao M
中科院分区：
文献类型：
--
作者：
Deng H;Kan A;Lyu N;He M;Huang X;Qiao S;Li S;Lu W;Xie Q;Chen H;Lai J;Chen Q;Jiang X;Liu S;Zhang Z;Zhao M
背景中性粒细胞在肿瘤发生发展中的作用存在争议。然而，程序性细胞死亡-1配体（PD-L1+）中性粒细胞的功能可能抑制抗肿瘤免疫的细胞毒性。在这项研究中，我们阐明了肿瘤微环境（TME）中PD-L1+中性粒细胞的刺激因子，并探索了通过抑制PD-L1+中性粒细胞来增强乐伐替尼在肝细胞癌中的作用的最佳组合。方法在患者样本、皮下和原位小鼠模型中，采用RNA测序和流式细胞术分析检测乐伐替尼治疗后的神经细胞浸润。从外周血和肿瘤组织中分离中性粒细胞和T细胞，并用磁珠纯化用于细胞毒性测定。采用Yellow Springs Instrument（YSI）公司生产的生化分析仪和Proteome Profiler细胞因子芯片检测代谢产物和细胞因子。使用通路抑制剂的体外筛选来鉴定可以减少PD-L1+中性粒细胞浸润的可能候选物。进一步的体内试验用于验证。结果乐伐替尼通过诱导TME中CXCL 2和CXCL 5的分泌增加中性粒细胞募集。进入TME后，中性粒细胞向N2表型极化。PD-L1表达同时上调。因此，乐伐替尼对肿瘤细胞的疗效受阻。PD-L1+中性粒细胞的增加与抑制性T细胞表型呈正相关。进一步研究表明，免疫细胞源性干扰素γ激活JAK/STAT 1通路和高浓度肿瘤源性乳酸激活MCT 1/NF-kB/考克斯-2通路可诱导PD-L1+中性粒细胞。考克斯-2抑制剂塞来昔布可明显抑制后者的作用。进一步的体内试验证实，塞来昔布可降低乳酸盐刺激的PD-L1+中性粒细胞的存活率，并促进乐伐替尼的抗肿瘤作用。结论PD-L1+中性粒细胞可降低T细胞的细胞毒活性。肿瘤源性乳酸盐通过MCT 1/NF-κB/考克斯-2途径诱导中性粒细胞表达PD-L1因此，考克斯-2抑制剂可以减少PD-L1+中性粒细胞，恢复T细胞的细胞毒性。这可能为乐伐替尼提供一种有效的补充。
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/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib. Conclusions PD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.
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影响因子：
11.2
作者：
Porta, Chiara;Consonni, Francesca Maria;Sica, Antonio
通讯作者：
Sica, Antonio
影响因子：
6.4
作者：
Gunda, Viswanath;Gigliotti, Benjamin;Parangi, Sareh
通讯作者：
Parangi, Sareh
影响因子：
45.3
作者：
Finn, Richard S.;Ikeda, Masafumi;Llovet, Josep M.
通讯作者：
Llovet, Josep M.
DOI：
10.1002/hep.31680
发表时间：
2021-07
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Li B;Severson E;Pignon JC;Zhao H;Li T;Novak J;Jiang P;Shen H;Aster JC;Rodig S;Signoretti S;Liu JS;Liu XS
通讯作者：
Liu XS