Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer
Abstract
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 Col3a1 and Col6a1 , formed multiple physical barriers surrounding tumor cells. Disruption of these barriers by collagenase or knockout of both Col3a1 and Col6a1 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 Col3a1 and Col6a1 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (38)
Manli Wang
Yiyun Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiangyu Pan
Key Laboratory of Green Printing, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
Bo Wang
Yuying Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiangmeng Luo
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiaofeng Deng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Li Liu
Xuelan Chen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiaoqian Zhai
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Baohong Wu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Qi Zhang
Yifeng Ren
Hospital of Chengdu University of Traditional Chinese Medicine
Jia Li
Xiaoyu Li
Fujun Cao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Yang Yang
Xintong Deng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Runhong Li
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Zhenghao Lu
Chengdu OrganoidMed Medical Laboratory, West China Health Valley
Ping Tan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Jingyao Chen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Yan Li
Yanyang Liu
Lung Cancer Treatment Center, West China Hospital, Sichuan University
Jiewei Liu
Lung Cancer Treatment Center, West China Hospital, Sichuan University
Yuan Wang
Hongxin Deng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Zhaoming Su
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Weiya Wang
Department of Pathology, West China Hospital, Sichuan University
Yongsheng Wang
Division of Thoracic Tumor Multimodality Treatment Cancer Center, West China Hospital, Sichuan University
Shengyong Yang
Chengjian Zhao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Jianxin Xue
Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Yuquan Wei
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Kang Zhang
Qi Biodesign, Beijing, China.
Feifei Na
Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Yu Liu
Chong Chen
Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University