Platelets upregulate tumor cell programmed death ligand 1 in an epidermal growth factor receptor-dependent manner in vitro.
Platelets upregulate tumor cell programmed death ligand 1 in an epidermal growth factor receptor-dependent manner in vitro.
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DOI：
10.1182/bloodadvances.2021006120
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发表时间：
2022-10-25
期刊：
影响因子：
7.5
通讯作者：
Battinelli, Elisabeth M.
中科院分区：
文献类型：
--
作者：
Guo, Qiuchen;Malloy, Michael W.;Roweth, Harvey G.;McAllister, Sandra S.;Italiano, Joseph E.;Battinelli, Elisabeth M.
程序性死亡配体1（PD-L1）是一种免疫检查点蛋白，可抑制细胞毒性T淋巴细胞，通常在癌症中过表达。由于良好的临床试验结果，免疫检查点抑制（ICI）是美国食品和药物管理局批准的免疫肿瘤治疗的一部分;然而，并非所有患者都能从ICI治疗中获益。高血小板-淋巴细胞比率与ICI治疗失败有关，但血小板是否在阻碍ICI反应中起作用尚不清楚。在这里，我们报告说，血小板与癌细胞系共培养增加了肿瘤细胞PD-L1的蛋白质和基因表达，而抗血小板药物（如阿司匹林和替格瑞洛）则降低了PD-L1的表达。血小板细胞因子阵列显示，包括干扰素-γ在内的公认的细胞因子不是血小板介导的PD-L1上调的主要调节因子。相反，高分子量表皮生长因子（EGF）在血小板中丰富，这导致肿瘤细胞PD-L1的上调。EGF中和抗体和西妥昔单抗（EGF受体[EGFR]单克隆抗体）均抑制血小板诱导的肿瘤细胞PD-L1增加，表明血小板以EGFR依赖性方式诱导肿瘤细胞PD-L1。我们的数据揭示了血小板在肿瘤免疫逃逸中的新机制，并需要进一步研究以确定靶向血小板是否可以改善ICI治疗反应。血小板可诱导肿瘤细胞PD-L1表达，提示血小板在肿瘤免疫逃逸中发挥作用。肿瘤细胞上血小板诱导的PD-L1上调由EGFR信号传导介导。
Programmed death ligand 1 (PD-L1) is an immune checkpoint protein that suppresses cytotoxic T lymphocytes and is often overexpressed in cancers. Due to favorable clinical trial results, immune checkpoint inhibition (ICI) is part of Food and Drug Administration approved immuno-oncology therapies; however, not all patients benefit from ICI therapy. High blood platelet-to-lymphocyte ratio has been associated with failure of ICI treatment, but whether platelets have a role in hindering ICI response is unclear. Here, we report that coculturing platelets with cancer cell lines increased protein and gene expression of tumor cell PD-L1, which was reduced by antiplatelet agents, such as aspirin and ticagrelor. Platelet cytokine arrays revealed that the well-established cytokines, including interferon-γ, were not the main regulators of platelet-mediated PD-L1 upregulation. Instead, the high molecular weight epidermal growth factor (EGF) is abundant in platelets, which caused an upregulation of tumor cell PD-L1. Both an EGF-neutralizing antibody and cetuximab (EGF receptor [EGFR] monoclonal antibody) inhibited platelet-induced increases in tumor cell PD-L1, suggesting that platelets induce tumor cell PD-L1 in an EGFR-dependent manner. Our data reveal a novel mechanism for platelets in tumor immune escape and warrant further investigation to determine if targeting platelets improves ICI therapeutic responses. Platelets induce PD-L1 expression in tumor cells, suggesting that platelets play a role in tumor immune escape. Platelet-induced PD-L1 upregulation on tumor cells is mediated by EGFR signaling.
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影响因子：
16.6
作者：
Robert, Caroline
通讯作者：
Robert, Caroline
GEPIA：用于癌症和正常基因表达谱和交互式分析的网络服务器。
影响因子：
14.9
作者：
Tang Z;Li C;Kang B;Gao G;Li C;Zhang Z
通讯作者：
Zhang Z
影响因子：
7.3
作者：
Goldberg J;Pastorello RG;Vallius T;Davis J;Cui YX;Agudo J;Waks AG;Keenan T;McAllister SS;Tolaney SM;Mittendorf EA;Guerriero JL
通讯作者：
Guerriero JL
癌症相关成纤维细胞通过分泌CXCL5促进小鼠癌细胞中PD-L1的表达
影响因子：
6.4
作者：
Li, Ziqian;Zhou, Jiawang;Du, Jun
通讯作者：
Du, Jun
影响因子：
82.9
作者：
Cerezo, Michael;Guemiri, Ramdane;Robert, Caroline
通讯作者：
Robert, Caroline