CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients
CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients
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DOI：
10.1073/pnas.0806075105
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发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
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作者：
Liakou, Chrysoula I.;Kamat, Ashish;Sharma, Padmanee
在用免疫抑制剂抗CTLA-4抗体治疗的一小部分癌症患者中已经报道了显著的抗肿瘤应答。迄今为止，所有临床试验（包括超过3，000名患者）都是在转移性疾病背景下进行的，这使得药物给药与临床结果相关，但对中间生物标志物的分析有限，无法表明药物是否影响了肿瘤微环境中的人体免疫反应。我们在6例局限性膀胱癌患者中进行了术前临床试验，该试验允许药物给药与血液和肿瘤组织中的生物标志物相关，但不允许与临床结果相关。我们发现，所有治疗患者的外周血和肿瘤组织中的CD 4 T细胞均显著增加了诱导型共刺激分子（ICOS）的表达。这些CD 4（+）ICOShi T细胞产生IFN-γ（IFN γ），并且可以识别肿瘤抗原NY-ESO-1。CD 4（+）ICOShi细胞的增加导致效应T细胞与调节T细胞的比率增加。据我们所知，这些是第一次报告的肿瘤组织和外周血中的免疫学变化，作为抗CTLA-4抗体治疗的结果，它们可用于指导这种药物的剂量和时间表，以改善临床反应。
Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent antiCTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4(+) ICOShi T cells produced IFN-gamma (IFN gamma) and could recognize the tumor antigen NY-ESO-1. Increase in CD4(+) ICOShi cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.