CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1.
CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1.
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DOI：
10.1158/1078-0432.ccr-15-2665
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发表时间：
2016-07-15
期刊：
影响因子：
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通讯作者：
Sunwoo JB
中科院分区：
文献类型：
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作者：
Lee Y;Shin JH;Longmire M;Wang H;Kohrt HE;Chang HY;Sunwoo JB
人类肿瘤由具有不同标志物表达和功能特性的异质细胞群组成。在头颈部鳞状细胞癌（SCCHN）中，CD44是与肿瘤发生、放射抗性和化学抗性增加相关的弹性细胞亚群的充分表征的标志物。有证据表明，这些细胞具有免疫抑制表型;然而，机制一直难以捉摸。使用原代人SCCHN肿瘤样本和患者来源的异种移植物，我们检查了肿瘤细胞亚群的表型，并研究了调节其免疫原性的机制。原代人SCCHN中的CD44+细胞被发现具有上皮-间充质（EMT）表型，当与自体CD8+肿瘤浸润T细胞一起培养时，其免疫原性低于CD44 −细胞。与CD44 −细胞相比，在CD44+细胞上观察到程序性死亡配体1（PD-L1）的选择性表达，并与CD44+细胞上STAT3的组成性磷酸化相关。重要的是，STAT3的抑制降低了CD44+细胞上PD-L1的表达。干扰素-γ（IFN γ）处理优先诱导CD44+细胞上进一步的PD-L1表达，并与IFN γ受体表达增强和STAT1磷酸化相关。最后，CD44+细胞的免疫原性降低被程序性死亡1（PD-1）受体的抗体阻断部分逆转，表明CD44+和CD44 −细胞之间PD-L1表达的差异具有生物学和临床相关性。我们的研究结果提供了一种机制，通过这种机制，长寿的CD44+肿瘤起始细胞可以选择性地逃避宿主免疫反应，并为SCCHN辅助治疗环境中靶向PD-1通路提供了理论基础。
Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immune suppressive phenotype; however, mechanisms have been elusive. Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity. CD44+ cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44− cells when cultured with autologous CD8+ tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44+ cells compared to CD44− cells and was associated with constitutive phosphorylation of STAT3 on CD44+ cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44+ cells. Interferon-γ (IFNγ) treatment preferentially induced even further PD-L1 expression on CD44+ cells and was associated with enhanced IFNγ receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44+ cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44+ and CD44− cells are biologically and clinically relevant. Our findings provide a mechanism by which long-lived CD44+ tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN.