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：

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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。