非常规抑制性 CD4Foxp3PD-1 T 细胞作为免疫检查点阻断活性的生物标志物。
Non-conventional Inhibitory CD4Foxp3PD-1 T Cells as a Biomarker of Immune Checkpoint Blockade Activity.
机构信息
Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Cancer Cell. 2018 Jun 11;33(6):1017-1032.e7. doi: 10.1016/j.ccell.2018.05.009.
A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4Foxp3 T cells expressing PD-1 (4PD1) and observed that 4PD1 accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1 increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1 reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1 inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (T)-like cells. Accordingly, anti-CTLA-4 activity is improved in T deficient mice.
相当一部分癌症患者对免疫检查点阻断治疗没有反应。为了更好地理解这些治疗方法的分子机制，我们探索了表达 PD-1 的 CD4Foxp3 T 细胞（4PD1）的作用，并观察到随着肿瘤负担的增加，4PD1 会在肿瘤内积聚。有趣的是，CTLA-4 阻断以剂量依赖的方式促进肿瘤内和外周 4PD1 的增加，而与 PD-1 阻断联合则减轻了这种作用并提高了抗肿瘤活性。我们发现，抗 PD-1 后缺乏有效的 4PD1 减少与预后不良相关。从机制上讲，我们提供的证据表明，小鼠和人类循环中和肿瘤内的 4PD1 以 PD-1/PD-L1 依赖的方式抑制 T 细胞功能，类似于滤泡辅助 T 细胞（Tfh）样细胞。因此，在 T 细胞缺陷小鼠中，抗 CTLA-4 的活性得到了改善。
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