单细胞图谱揭示抗PD-1治疗的非小细胞肺癌中的免疫异质性。

A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer.

作者信息

Liu Zedao, Yang Zhenlin, Wu Junqi, Zhang Wenjie, Sun Yuxuan, Zhang Chao, Bai Guangyu, Yang Li, Fan Hongtao, Chen Yawen, Zhang Lei, Jiang Benyuan, Liu Xiaoyan, Ma Xiaoshi, Tang Wei, Liu Chang, Qu Yang, Yan Lixu, Zhao Deping, Wu Yilong, He Shun, Xu Long, Peng Lishan, Chen Xiaowei, Zhou Bolun, Zhao Liang, Zhao Zhangyi, Tan Fengwei, Zhang Wanting, Yi Dingcheng, Li Xiangjie, Gao Qianqian, Zhang Guangjian, Wang Yongjie, Yang Minglei, Fu Honghao, Guo Yongjun, Hu Xueda, Cai Qingyuan, Qi Lu, Bo Yufei, Peng Hui, Tian Zhigang, She Yunlang, Zou Chang, Zhu Linnan, Cheng Sijin, Zhang Yi, Zhong Wenzhao, Chen Chang, Gao Shugeng, Zhang Zemin

机构信息

Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing 100871, China.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

出版信息

Cell. 2025 May 29;188(11):3081-3096.e19. doi: 10.1016/j.cell.2025.03.018. Epub 2025 Mar 26.

DOI:10.1016/j.cell.2025.03.018

PMID:40147443

Abstract

Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of FGFBP2 NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher CCR8 Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and CCR8 Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management.

摘要

抗程序性死亡蛋白（PD）-(L)1治疗是非小细胞肺癌（NSCLC）的标准治疗方法，但患者对相同治疗方案的反应存在差异。肿瘤免疫微环境（TIME）与免疫治疗反应相关，但其潜在的异质性治疗结果仍未得到充分探索。我们应用单细胞RNA和TCR测序（scRNA/TCR-seq）分析了234例接受新辅助化疗免疫治疗后的NSCLC患者的手术肿瘤样本。分析揭示了五种不同的TIME亚型，其主要病理反应（MPR）率各不相同。MPR患者的FGFBP2自然杀伤细胞/NK样T细胞、记忆B细胞或效应T细胞水平升高，而非MPR患者的CCR8调节性T细胞水平更高。T细胞克隆扩增分析揭示了非MPR患者的异质性，其特征是与终末耗竭T细胞相关的细胞和CCR8调节性T细胞的不同扩增。前体耗竭T细胞（Texp细胞）与无复发生存相关，确定了一个尽管缺乏MPR但复发风险降低的患者亚组。我们的研究剖析了化疗免疫治疗反应中的TIME异质性，为NSCLC的管理提供了见解。