Heterogeneity‐induced NGF‐NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti‐tumor immunotherapy with PD‐1 mAb in hepatocellular carcinoma

Abstract Background The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. Methods Cells were separated from the single‐cell RNA‐sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell‐cell communication. Flow cytometry, EDU staining, H3‐Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF‐NGFR promoting proliferation. Results The present study has revealed that during the process of T‐cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF‐NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1‐mediated inhibition of unclear trans‐localization of PREX1. Furthermore, PD‐1 mAb acts synergistically with the NGF‐NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF‐NGFR communication was positively correlates with the PD‐1/PDL‐1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. Conclusion Inefficiency in NGF‐NGFR communication impairs PD‐1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.