T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma
T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma
复制标题
DOI：
10.1172/jci.insight.122092
复制
发表时间：
2018-07-12
期刊：
影响因子：
8
通讯作者：
Jaffee, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Hopkins, Alexander C.;Yarchoan, Mark;Jaffee, Elizabeth M.
背景免疫检查点抑制剂为一部分患者提供了显著的临床益处，但需要新的预后标志物来预测哪些患者会有反应。这项研究的目的是确定患者T细胞库的特征是否可以提供免疫治疗机制的见解，同时也预测结果。我们检查了25名接受伊匹单抗联合或不联合GVAX（一种胰腺癌疫苗）治疗的转移性胰腺癌患者外周血中的T细胞受体（TCR），以及32名接受GVAX和表达间皮素的单核细胞增生李斯特菌联合或不联合纳武单抗治疗的患者的外周血和肿瘤活检组织。然后检验这些数据库的统计数据与临床应答和治疗组的相关性。我们证明，首先，大多数接受这些治疗的患者经历了外周TCR库的净多样化。第二，接受伊匹单抗的患者在其谱系中经历了更大的变化，特别是与GVAX组合。最后，低基线克隆性和治疗后大量扩增的克隆与接受ipilimumab的患者的生存期显著延长相关，但与接受nivolumab的患者无关。我们表明，这些疗法对外周库具有可测量的不同影响，与其作用机制一致，并证明TCR库分析作为接受免疫治疗的胰腺癌患者临床反应的生物标志物的潜力。此外，我们的结果表明，测试抗CTLA-4和抗PD-1抗体的顺序施用以实现最佳治疗益处。
BACKGROUND. Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes.METHODS. We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group.RESULTS. We demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab.CONCLUSIONS. We show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti-CTLA-4 and anti-PD-1 antibodies to achieve optimal therapeutic benefit.