T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
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DOI：
10.1038/nature22079
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发表时间：
2017-05-04
期刊：
影响因子：
64.8
通讯作者：
Wherry EJ
中科院分区：
文献类型：
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作者：
Huang AC;Postow MA;Orlowski RJ;Mick R;Bengsch B;Manne S;Xu W;Harmon S;Giles JR;Wenz B;Adamow M;Kuk D;Panageas KS;Carrera C;Wong P;Quagliarello F;Wubbenhorst B;D'Andrea K;Pauken KE;Herati RS;Staupe RP;Schenkel JM;McGettigan S;Kothari S;George SM;Vonderheide RH;Amaravadi RK;Karakousis GC;Schuchter LM;Xu X;Nathanson KL;Wolchok JD;Gangadhar TC;Wherry EJ
尽管基于程序性细胞死亡1（PD-1）阻断的单药治疗在人黑素瘤中取得了成功，但大多数患者没有经历持久的临床益处。肿瘤中预先存在的T细胞浸润和/或PD-L1的存在可用作临床应答的指标;然而，尚未广泛探索用于了解PD-1阻断机制的基于血液的分析。在这里，我们使用PD-1靶向抗体pembrolizumab治疗前后IV期黑色素瘤患者外周血的免疫分析，并确定循环耗竭表型CD 8 T细胞（Tex细胞）的药效学变化。大多数患者表现出对pembrolizumab的免疫应答。许多患者的临床失败不仅仅是由于无法诱导免疫复苏，而是由于T细胞复苏和肿瘤负荷之间的不平衡。与治疗前肿瘤负荷相关的循环Tex细胞的复苏幅度与临床应答相关。通过集中分析与治疗前疾病负荷校准的机制相关的循环T细胞亚群，我们确定了临床上可获得的对PD-1阻断反应的潜在治疗中预测因子。
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.