Lee Yunqin, Shin June Ho, Longmire Michelle, Wang Hua, Kohrt Holbrook E, Chang Howard Y, Sunwoo John B
Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford, California. Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Stanford Cancer Institute, Stanford, California. Program in Epithelial Biology, Stanford Cancer Institute, Stanford, California.
Clin Cancer Res. 2016 Jul 15;22(14):3571-81. doi: 10.1158/1078-0432.CCR-15-2665. Epub 2016 Feb 10.
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 immunosuppressive 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 with 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. 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. Clin Cancer Res; 22(14); 3571-81. ©2016 AACR.
人类肿瘤由具有不同标志物表达和功能特性的异质性细胞群体组成。在头颈部鳞状细胞癌（SCCHN）中，CD44是一个特征明确的细胞亚群标志物，该亚群细胞具有更强的肿瘤发生能力、放射抗性和化学抗性。有证据表明这些细胞具有免疫抑制表型；然而，其机制尚不清楚。
我们使用原发性人类SCCHN肿瘤样本和患者来源的异种移植模型，研究了肿瘤细胞亚群的表型，并探究了调节其免疫原性的机制。
在原发性人类SCCHN中，CD44(+)细胞具有上皮-间质转化（EMT）表型，与自体CD8(+)肿瘤浸润性T细胞共培养时，其免疫原性低于CD44(-)细胞。与CD44(-)细胞相比，CD44(+)细胞上观察到程序性死亡配体1（PD-L1）的选择性表达，且与CD44(+)细胞上STAT3的组成型磷酸化有关。重要的是，抑制STAT3可降低CD44(+)细胞上PD-L1的表达。IFNγ处理优先进一步诱导CD44(+)细胞上的PD-L1表达，并与增强的IFNγ受体表达和STAT1磷酸化有关。最后，程序性死亡1（PD-1）受体的抗体阻断部分逆转了CD44(+)细胞免疫原性的降低，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，通过该机制，长寿的CD44(+)肿瘤起始细胞可以选择性逃避宿主免疫反应，并为在SCCHN辅助治疗中靶向PD-1途径提供了理论依据。临床癌症研究；22(14)；3571 - 81。©2016美国癌症研究协会。
