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

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

doi:10.1038/s41588-024-01998-y

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

Nat Genet. 2025 Jan;57(1):126-139. doi: 10.1038/s41588-024-01998-y. Epub 2024 Dec 10.

Authors

Yilv Yan^#¹, Dongqing Sun^#^{2

3}, Junjie Hu^#¹, Yue Chen^#⁴, Liangdong Sun¹, Huansha Yu¹, Yicheng Xiong¹, Zhida Huang¹, Haoran Xia¹, Xinsheng Zhu¹, Dongliang Bian¹, Fenghuan Sun¹, Likun Hou⁵, Chunyan Wu⁵, Orion R Fan⁶, Haiyang Hu⁷, An Zeng⁸, Lele Zhang⁹, Yi Eve Sun¹⁰, Chenfei Wang^{11

12

13

14}, Peng Zhang^{15

16}

Affiliations

¹ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, China.
³ Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁴ State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁵ Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
⁶ Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
⁷ Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
⁸ State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. azeng@sibcb.ac.cn.
⁹ Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. zhanglele@tongji.edu.cn.
¹⁰ Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China. yi.eve.sun@gmail.com.
¹¹ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, China. 08chenfeiwang@tongji.edu.cn.
¹² Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. 08chenfeiwang@tongji.edu.cn.
¹³ National Key Laboratory of Autonomous Intelligent Unmanned Systems, Tongji University, Shanghai, China. 08chenfeiwang@tongji.edu.cn.
¹⁴ Frontier Science Center for Intelligent Autonomous Systems, Tongji University, Shanghai, China. 08chenfeiwang@tongji.edu.cn.
¹⁵ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. zhangpeng1121@tongji.edu.cn.
¹⁶ Department of Thoracic Surgery, The First Affiliated Hospital of Shihezi University Medical College, Shihezi, China. zhangpeng1121@tongji.edu.cn.

^# Contributed equally.

PMID: 39658657
DOI: 10.1038/s41588-024-01998-y

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.

MeSH terms

Cancer-Associated Fibroblasts / metabolism
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Drug Resistance, Neoplasm* / genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy / methods
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Multiomics
Prognosis
Single-Cell Analysis
Transcriptome
Tumor Microenvironment* / genetics

Substances

Immune Checkpoint Inhibitors

Abstract

MeSH terms

Substances

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