Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Department of Medicine, Harvard Medical School, Boston, MA.
Blood Adv. 2022 Oct 25;6(20):5668-5675. doi: 10.1182/bloodadvances.2021006120.
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.
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，并且在癌症中经常过表达。由于临床试验结果良好，免疫检查点抑制（ICI）是食品和药物管理局批准的免疫肿瘤疗法的一部分；然而，并非所有患者都从 ICI 治疗中受益。高血小板与淋巴细胞比值与 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，我们报告称，血小板与癌细胞系共培养会增加肿瘤细胞 PD-L1 的蛋白和基因表达，而抗血小板药物，如阿司匹林和替格瑞洛，可降低 PD-L1 的表达。血小板细胞因子阵列显示，干扰素-γ等已确立的细胞因子并非血小板介导的 PD-L1 上调的主要调节剂。相反，血小板中富含高分子量表皮生长因子（EGF），它导致肿瘤细胞 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。
