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.