Proliferation of PD-1+CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients
Proliferation of PD-1+CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients
复制标题
DOI：
10.1073/pnas.1705327114
复制
发表时间：
2017-05-09
影响因子：
11.1
通讯作者：
Ramalingam, Suresh S.
中科院分区：
文献类型：
--
作者：
Kamphorst, Alice O.;Pillai, Rathi N.;Ramalingam, Suresh S.
慢性感染和癌症中耗尽的T细胞持续表达抑制性受体程序性细胞死亡1（PD-1）。阻断PD-1通路的疗法在大量晚期癌症患者中显示出有希望的临床结果。尽管如此，对PD-1阻断在癌症患者中诱导的免疫应答缺乏更好的理解。预测性生物标志物的鉴定是该领域的优先事项，但外周血分析是否可以提供生物标志物来监测或预测患者对治疗的反应仍有待解决。在这项研究中，我们分析了接受PD-1靶向治疗的晚期非小细胞肺癌（NSCLC）患者（n = 29）的纵向血液样本。我们检测到治疗后Ki-67+ PD-1+ CD 8 T细胞的增加与70%的患者相似，并且大多数应答在第一或第二个治疗周期后诱导。这种T细胞活化不是不加区别的，因为我们观察到对EBV特异性CD 8 T细胞的影响很小，这表明应答细胞可能是肿瘤特异性的。这些增殖的CD 8 T细胞具有效应子样表型（HLA-DR+、CD 38+、Bcl-2（lo）），表达共刺激分子（CD 28、CD 27、ICOS），并且具有高水平的PD-1和CTLA-4的共表达。我们发现，70%的疾病进展患者延迟或缺乏PD-1+ CD 8 T细胞应答，而80%的临床获益患者在治疗开始后4周内表现出PD-1+ CD 8 T细胞应答。我们的研究结果表明，外周血分析可能为NSCLC患者对PD-1靶向治疗的反应提供有价值的见解。
Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients' responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non-small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1-targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in similar to 70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2(lo)), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients' responses to PD-1-targeted therapies.