Apatinib-induced transcriptomic remodeling in the multicellular ecosystem of gastric cancer patient-derived xenografts enhances anti-PD-1 immunotherapy

Apatinib can clinically enhance anti-PD-1 immunotherapy for advanced gastric cancer (GC), but the complexity of GC immunosuppression still hampers the development of precision immunotherapy. Here, we profiled the transcriptomes of 34,182 single cells from gastric cancer patient-derived xenografts (GC-PDXs) from humanized mouse models treated with vehicle, nivolumab, or nivolumab plus apatinib. The tumor microenvironment (TME) showed activation of multiple types of immunosuppression-associated transcriptomic remodeling after nivolumab monotherapy, and this remodeling could be substantially reduced by combined apatinib treatment. Notably, excessive expression of CXCL5 in the CellCycle malignant epithelium, induced by anti-PD-1 immunotherapy, was found to be a key driver of tumor-associated neutrophil (TAN) recruitment in the TME through the CXCL5/CXCR2 axis. We further revealed that a high level of the protumor TAN signature might lead to anti-PD-1 immunotherapy-related progressive disease (PD) and poor cancer prognosis. The diversity and plasticity of tumor-infiltrating macrophages and fibroblasts were then investigated, and we observed immunotherapy-induced enrichment of subpopulations reported to be associated with tumor progression and immunosuppression. Molecular and functional analyses in cell-derived xenograft (CDX) mouse models directly confirmed the positive in vivo therapeutic effect of targeting the CXCL5/CXCR2 axis during anti-PD-1 immunotherapy. Altogether, our study elucidates GC immunosuppression-associated transcriptomic remodeling during anti-PD-1-based immunotherapy and highlights multiple potential targets for overcoming checkpoint immunotherapy resistance.