A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer
Zedao Liu, Zhenlin Yang, Junqi Wu, Wenjie Zhang, Yuxuan Sun, Chao Zhang, Guangyu Bai, Yang Li, Hongtao Fan, Ya‐Wen Chen, Lei Zhang, Ben‐Yuan Jiang, Xiaoyan Liu, Xiaoshi Ma, Wei Tang, Chang Liu, Yang Qu, Li‐Xu Yan, Deping Zhao, Yi‐Long Wu, Shun He, Long Xu, Lishan Peng, Xiaowei Chen, Bolun Zhou, Liang Zhao, Zhangyi Zhao, Fengwei Tan, Wanting Zhang, Dingcheng Yi, Xiangjie Li, Qianqian Gao, Guangjian Zhang, Yongjie Wang, Minglei Yang, Honghao Fu, Yongjun Guo, Xueda Hu, Qingyuan Cai, Qi Lu, Yufei Bo, Hui Peng, Zhigang Tian, Chang Chen, Chang Zou, Linnan Zhu, Sijin Cheng, Yi Zhang, Wen‐Zhao Zhong, Chen Chang, Shugeng Gao, Zemin Zhang
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.