A Cancer Vaccine Induces Expansion of NY-ESO-1-Specific Regulatory T Cells in Patients with Advanced Melanoma
A Cancer Vaccine Induces Expansion of NY-ESO-1-Specific Regulatory T Cells in Patients with Advanced Melanoma
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DOI：
10.1371/journal.pone.0048424
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发表时间：
2012-10-26
期刊：
影响因子：
3.7
通讯作者：
Chen, Weisan
中科院分区：
文献类型：
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作者：
Ebert, Lisa M.;MacRaild, Sarah E.;Chen, Weisan
癌症疫苗被设计为扩增具有效应子功能的肿瘤抗原特异性T细胞。然而，它们也可能无意中扩增调节性T细胞（Treg），这可能严重阻碍临床疗效。为了解决这种可能性，我们开发了一种新的检测方法，根据TCR接合后表面CD 3的下调来检测抗原特异性Treg，并使用这种方法在用NY-ESO-1/ISCOMATRIX（TM）癌症疫苗治疗的黑色素瘤患者中筛选对NY-ESO-1肿瘤抗原特异性的Treg。所有受试患者均具有对血液中至少一个NY-ESO-1表位具有特异性的Treg（CD 25（亮）FoxP 3（+）CD 127（阴性））。引人注目的是，与治疗前样品的比较显示，许多这些反应是通过疫苗接种诱导或加强的。最常检测到的应答是针对HLA-DP 4限制性NY-ESO-1（157-170）表位，其也被效应T细胞识别。值得注意的是，对NY-ESO-1（115-132）肽内的HLA-DR限制性表位具有特异性的功能性Treg也在肿瘤组织中以高频率被鉴定，这表明NY-ESO-1特异性Treg可以抑制局部抗肿瘤免疫应答。总之，我们的数据为癌症疫苗在晚期癌症背景下扩增肿瘤抗原特异性Treg的能力提供了令人信服的证据，这一发现应在未来癌症疫苗临床试验的设计中予以认真考虑。
Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX (TM) cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.