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

Apatinib remodels the immunosuppressive tumor ecosystem of gastric cancer enhancing anti-PD-1 immunotherapy

2023

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.

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