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Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer.
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2020-03-15 , DOI: 10.1158/1078-0432.ccr-19-2931
Jiajia Zhang 1, 2 , Zhicheng Ji 3 , Justina X Caushi 1, 2 , Margueritta El Asmar 1, 2 , Valsamo Anagnostou 1, 2 , Tricia R Cottrell 1, 2, 4 , Hok Yee Chan 1, 2 , Prerna Suri 1, 2 , Haidan Guo 1, 2 , Taha Merghoub 5 , Jamie E Chaft 5 , Joshua E Reuss 1, 2 , Ada J Tam 1, 2 , Richard L Blosser 1, 2 , Mohsen Abu-Akeel 5 , John-William Sidhom 1, 2 , Ni Zhao 3 , Jinny S Ha 2, 6 , David R Jones 7 , Kristen A Marrone 1, 2 , Jarushka Naidoo 1, 2 , Edward Gabrielson 1, 2 , Janis M Taube 1, 2, 4 , Victor E Velculescu 1, 2 , Julie R Brahmer 1, 2 , Franck Housseau 1, 2 , Matthew D Hellmann 5 , Patrick M Forde 1, 2 , Drew M Pardoll 1, 2 , Hongkai Ji 3 , Kellie N Smith 1, 2
Affiliation  

PURPOSE Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. EXPERIMENTAL DESIGN T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode. RESULTS Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor. CONCLUSIONS Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity.See related commentary by XXX, p. XXX.

中文翻译:

T 细胞克隆动力学的隔室分析作为对可切除非小细胞肺癌新辅助 PD-1 阻断的病理反应的函数。

目的 新辅助 PD-1 阻断剂是可切除的非小细胞肺癌 (NSCLC) 的一种有前途的治疗方法,但有助于肿瘤消退的免疫机制和反应的生物标志物尚不清楚。使用来自 II 期临床试验 (NCT02259621) 的配对肿瘤/血液样本,我们探讨了外周 T 细胞克隆型动力学是否可以作为对新辅助 PD-1 阻断反应的生物标志物。实验设计 对接受新辅助 PD-1 阻断治疗的可切除 NSCLC 患者的系列外周血、肿瘤和正常肺样本进行 T 细胞受体 (TCR) 测序。我们通过使用 TCR 作为分子条形码,探索了外周和肿瘤隔室中 T 细胞库响应新辅助 PD-1 阻断的时间动态。结果 较高的肿瘤内 TCR 克隆性与手术时残留肿瘤百分比降低相关,具有主要病理反应的肿瘤(MPR;新辅助治疗后残留肿瘤 <10%)的 TCR 库具有较高的克隆性和更多的肿瘤-与没有 MPR 的肿瘤相比,外周血浸润克隆型。此外,MPR 患者的治疗后肿瘤床富含 T 细胞克隆,这些 T 细胞克隆在抗 PD-1 启动后 2 至 4 周之间外周扩增,并且这些克隆型占据的肿瘤内空间与残留肿瘤百分比呈负相关。结论 我们的研究表明,肿瘤和血液之间的 T 细胞克隆交换代表了对新辅助免疫治疗的病理反应的关键相关性,并表明外周可能是以前未被充分认识的有效抗肿瘤免疫的起源区室。参见 XXX 的相关评论,第 10 页。XXX。
更新日期:2020-04-21
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