Tumor-infiltrating platelets recruit neutrophils to promote tumor growth through the 5-HIAA–GPR35–ERK1/2 axis in Hepatocellular Carcinoma
Menée à l'aide de modèles murins et d'échantillons tumoraux provenant de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel les plaquettes infiltrant les tumeurs favorisent la croissance tumorale via le recrutement des neutrophiles et la voie de signalisation impliquant l'acide 5-hydroxyindoleacétique, le récepteur GPR35 et les kinases ERK1/2
Tumor-associated neutrophils (TANs) promote tumor growth and metastasis in hepatocellular carcinoma (HCC). Platelets can activate neutrophils and contribute to inflammation and organ damage; however, the relationship between TANs and platelets in HCC remains unclear. We performed multiplex immunohistochemistry and found that tumor-infiltrating platelets and TANs exhibited similar spatial distributions in patient-derived HCC samples. Then, a transwell migration assay demonstrated that supernatants from platelets co-cultured with HCC cells enhanced neutrophil migration in vitro, compared with supernatants from platelets or HCC cells cultured alone. Subsequent metabolomics analysis and in vitro and in vivo validation revealed that platelet-derived 5-HIAA promoted neutrophil migration via GPR35. Furthermore, in Hepa1-6 mouse models of HCC, GPR35+ neutrophils were found to facilitate HCC growth. Analysis of human HCC single-cell RNA-seq data and mouse neutrophil bulk RNA-seq data revealed significant upregulation of the MAPK signaling pathway and pathways associated with neutrophil migration and cytokine production in GPR35+ neutrophils. Finally, in vitro experiments demonstrated that 5-HIAA activated the ERK1/2 pathway, enhanced pro-tumor cytokine production and promoted HCC cell growth via GPR35, all of which were suppressed by the GPR35 inhibitor CID2745687. Together, these data indicate that tumor-infiltrating platelets recruit neutrophils to promote tumor growth through the 5-HIAA–GPR35–ERK1/2 axis in HCC.
Cancer Immunology Research , résumé, 2026