Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer
Immunotherapy has become the standard treatment for many types of cancers, but an increasing number of patients who initially respond to these treatments develop acquired immunotherapy resistance (AIR). Here, we recapitulated the entire process of immunotherapy from response to AIR in mice with non-small cell lung cancer (NSCLC). With implanted tumor organoids derived from these models and serial transplants, we demonstrated that tumor cell-intrinsic mechanisms contributed significantly to AIR. Single-cell RNA sequencing and electron microscope assays revealed that resistant tumor cell-expressing collagens, including <i>Col3a1</i> and <i>Col6a1</i>, formed multiple physical barriers surrounding tumor cells. Disruption of these barriers by collagenase or knockout of both <i>Col3a1</i> and <i>Col6a1</i> in tumor cells could sensitize the tumors of AIR. Mechanistically, the TGFβ pathway was upregulated upon immunotherapy, and treatment with TGFβ significantly increased the expression levels of both <i>Col3a1</i> and <i>Col6a1</i> in tumor cells. COL3A1 formed a castle-like barrier for a cluster of tumor cells and prevented T cell infiltration, while COL6A1 formed an armor-like barrier surrounding individual tumor cells to protect them against direct T cell attack. Our data reveal a tumor cell-intrinsic mechanism of AIR, mediated by collagen-containing physical barriers, which immediately suggests a clinical treatment option.
Authors
- Hongxin Deng
- Jiewei Liu
- Xiangyu Pan (ORCID: https://orcid.org/0000-0002-2537-6616)
- Xiaofeng Deng (ORCID: https://orcid.org/0009-0009-0158-155X)
- Chengjian Zhao (ORCID: https://orcid.org/0000-0003-0624-5263)
- Xintong Deng
- Zhenghao Lu
- Feifei Na
- Yifeng Ren (ORCID: https://orcid.org/0000-0003-2976-4250)
- Zhaoming Su (ORCID: https://orcid.org/0000-0002-9279-1721)
- Yuquan Wei (ORCID: https://orcid.org/0000-0002-6211-3217)
- Baohong Wu
- Ping Tan (ORCID: https://orcid.org/0000-0001-5916-5588)
- Yuan Wang (ORCID: https://orcid.org/0000-0002-6324-6134)
- Chong Chen (ORCID: https://orcid.org/0000-0002-6787-0495)
- Yongsheng Wang
- Qi Zhang (ORCID: https://orcid.org/0000-0001-9916-8919)
- Wei Wang (ORCID: https://orcid.org/0009-0003-7539-9394)
- Yang Yang (ORCID: https://orcid.org/0000-0002-6899-924X)
- Yan Li (ORCID: https://orcid.org/0000-0002-3134-7715)
- Yuying Wang (ORCID: https://orcid.org/0000-0001-9762-8563)
- Li Liu (ORCID: https://orcid.org/0000-0002-3275-2499)
- Ran Li (ORCID: https://orcid.org/0000-0002-8139-6080)
- Kang Zhang (ORCID: https://orcid.org/0000-0002-4549-1697)
- Xiaoling Luo (ORCID: https://orcid.org/0009-0004-9640-7899)
- Li Jia (ORCID: https://orcid.org/0000-0002-9450-7376)
- Fujun Cao
- Xiaoyu Li (ORCID: https://orcid.org/0000-0003-3890-8332)
- Jingyao Chen (ORCID: https://orcid.org/0000-0001-8810-6229)
- Xiaoqian Zhai (ORCID: https://orcid.org/0009-0003-1241-1595)
- Shengyong Yang
- Yiyun Wang (ORCID: https://orcid.org/0000-0002-6141-3613)
- Weiya Wang (ORCID: https://orcid.org/0000-0003-3927-6218)
- Xuelan Chen
- Jianxin Xue
- Manli Wang (ORCID: https://orcid.org/0000-0002-0679-5997)
Institutions
- Macau University of Science and Technology (MO)
- Chengdu Medical College (CN)
- Sichuan University (CN)
- West China Medical Center of Sichuan University (CN)
- West China Second University Hospital of Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Sichuan Cancer Hospital (CN)
- State Key Laboratory of Biotherapy
- Chengdu University of Traditional Chinese Medicine (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1073/pnas.2500019122
- Citations
- 7
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 5.58