NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

Abstract The number of T cells that infiltrate tumor tissues in hepatocellular carcinoma (HCC) is significantly low. The molecular mechanism underlying T cell proliferation in tumor tissues is poorly understood. The present study revealed that during the process of T cell infiltration from adjacent tissues to tumor tissues, the NGF-NGFR communication inefficiency occurred in the tumor tissues of HCC patients. Importantly, the tumor cell-secreted NGF interacted with NGFR on the membranes of the infiltrated T cells, which promoted proliferation of these cells through mitotic spindle signal activation. Mechanistically, the mitotic spindle signal activation promoted the proliferation was mediated by the HDAC1 unclear trans-localization-inhibited PREX1 expression. Further, PD-1 mAb acted synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse model and HCC patients. In addition, NGF–NGFR communication was positively correlated with the PD-1/PDL-1 expression. However, NGF and NGFR expressions were low in tumor tissues, which was responsible for the incursive clinicopathological features and the disappointing prognosis in HCC patients. Collectively, the results suggested that NGF-NGFR communication inefficiency impaired PD-1 mAb immunotherapy and could, therefore, be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.