Apatinib remodels the immunosuppressive tumor ecosystem of gastric cancer enhancing anti-PD-1 immunotherapy
Qicong Luo,
Zinan Dong,
Wen Xie,
Xiaoteng Fu,
Lingyun Lin,
Qiang Zeng,
Yinggang Chen,
Guodong Ye,
Maoli Chen,
Huiyu Hu,
Lin Wang,
Yuanyuan Xie,
Wangyu Cai
Affiliations
Qicong Luo
Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
Zinan Dong
Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China
Wen Xie
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China
Xiaoteng Fu
State Key Laboratory Breeding Base of Marine Genetic Resources; Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China
Lingyun Lin
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China
Qiang Zeng
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China
Yinggang Chen
Department of Gastrointestinal Surgery, Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, Shenzhen 518116, China
Guodong Ye
Xiamen LifeInt Technology Co., Ltd, Xiamen 361026, China
Maoli Chen
Xiamen LifeInt Technology Co., Ltd, Xiamen 361026, China
Huiyu Hu
Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China
Lin Wang
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Department of Oncology, Zhongshan Hospital of Xiamen University, Xiamen 361004, China; Corresponding author
Yuanyuan Xie
Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China; Department of Neurosurgery, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China; Corresponding author
Wangyu Cai
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, China; Corresponding author
Summary: Apatinib has been shown to clinically enhance anti-PD-1 immunotherapy for advanced gastric cancer (GC). However, the complexity of GC immunosuppression remains a challenge for precision immunotherapy. Here, we profile the transcriptomes of 34,182 single cells from GC patient-derived xenografts of humanized mouse models treated with vehicle, nivolumab, or nivolumab plus apatinib. Notably, excessive expression of CXCL5 in the CellCycle malignant epithelium, induced by anti-PD-1 immunotherapy and blocked by combined apatinib treatment, is found to be a key driver of tumor-associated neutrophil (TAN) recruitment in the tumor microenvironment through the CXCL5/CXCR2 axis. We further show that the protumor TAN signature is associated with anti-PD-1 immunotherapy-related progressive disease and poor cancer prognosis. Molecular and functional analyses in cell-derived xenograft models confirm the positive in vivo therapeutic effect of targeting the CXCL5/CXCR2 axis during anti-PD-1 immunotherapy. Altogether, our study elucidates the GC immunosuppressive landscape in anti-PD-1 immunotherapy and highlights potential targets for overcoming checkpoint immunotherapy resistance.
