CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.
CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.
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DOI：
10.1158/0008-5472.can-14-2788
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发表时间：
2015-06-01
期刊：
影响因子：
11.2
通讯作者：
Ferris RL
中科院分区：
文献类型：
--
作者：
Jie HB;Schuler PJ;Lee SC;Srivastava RM;Argiris A;Ferrone S;Whiteside TL;Ferris RL
EGFR靶向抗体西妥昔单抗对头颈癌（HNC）有效，但仅在15 - 20%的患者中有效，并且西妥昔单抗介导的细胞免疫的可变性和程度尚未完全了解。我们假设调节性T细胞（Treg）可能对西妥昔单抗治疗个体的抗肿瘤免疫产生功能和临床影响。在一项新型新辅助、单药西妥昔单抗临床试验中，分析了西妥昔单抗治疗的HNC患者的循环和肿瘤微环境中Treg和NK细胞的频率、免疫抑制表型和活化状态。值得注意的是，西妥昔单抗治疗增加了表达CTLA-4、CD 39和TGF-β的CD 4 + FOXP 3+肿瘤内Treg的频率。这些Treg抑制西妥昔单抗介导的ADCC，并且它们的存在与两个前瞻性临床试验队列中的不良临床结果相关。西妥昔单抗在体外扩增CTLA-4+ F0 XP 3 + Treg，部分通过诱导DC成熟，与TGF-β和TCR触发组合。重要的是，西妥昔单抗激活的NK细胞选择性地消除肿瘤内Treg，但保留效应T细胞。在离体测定中，伊匹单抗靶向CTLA-4+ Treg并恢复介导ADCC的NK细胞的细胞溶解功能。综上所述，我们的结果表明，Treg介导的抑制的差异有助于西妥昔单抗治疗的临床反应，这表明通过添加伊匹单抗或其他Treg消融策略来促进抗肿瘤免疫力。
The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNC), but in only 15 – 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype and activation status of Treg and NK cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated HNC patients enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4+FOXP3+ intratumoral Treg expressing CTLA-4, CD39 and TGF-β. These Treg suppressed cetuximab-mediated ADCC and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4+FOXP3+ Treg in vitro, in part by inducing DC maturation, in combination with TGF-β and TCR triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4+ Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote anti-tumor immunity.