同济大学张鹏等研究人员合作发现，多组学分析揭示与非小细胞肺癌免疫化疗耐药性相关的因素。2024年12月10日，《自然—遗传学》杂志在线发表了这项成果。

研究人员通过分析来自19名患者的肿瘤单细胞转录组和空间解析转录组，表征了非小细胞肺癌（NSCLC）肿瘤微环境（TME）中的肿瘤细胞状态和空间细胞组成，涵盖了免疫检查点抑制（ICB）-化疗治疗前后的肿瘤样本。研究人员发现，肿瘤细胞和分泌磷蛋白1阳性的巨噬细胞，与胶原蛋白XI α1链阳性的癌症相关成纤维细胞相互作用，刺激了胶原纤维在肿瘤边界的沉积和缠结，阻碍了T细胞的渗透，导致预后不良。

研究人员还揭示了TME中三级淋巴结构（TLS）的不同状态。活化的TLS与改善的预后相关，而缺氧微环境似乎抑制了TLS的发展，并与较差的预后相关。该研究为NSCLC ICB-化疗反应性对应的不同细胞和分子组分，提供了新的见解，这将有助于未来个性化免疫化疗的开展。

据悉，尽管ICB疗法已经改变了NSCLC的治疗范式，但许多患者仍然对治疗产生耐药性。

附：英文原文

Title: Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung cancer

Author: Yan, Yilv, Sun, Dongqing, Hu, Junjie, Chen, Yue, Sun, Liangdong, Yu, Huansha, Xiong, Yicheng, Huang, Zhida, Xia, Haoran, Zhu, Xinsheng, Bian, Dongliang, Sun, Fenghuan, Hou, Likun, Wu, Chunyan, Fan, Orion R., Hu, Haiyang, Zeng, An, Zhang, Lele, Sun, Yi Eve, Wang, Chenfei, Zhang, Peng

Issue&Volume: 2024-12-10

Abstract: Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB–chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB–chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy.

DOI: 10.1038/s41588-024-01998-y

Source: https://www.nature.com/articles/s41588-024-01998-y