Downregulation of TPX2 impairs the antitumor activity of CD8+ T cells in hepatocellular carcinoma

Abstract

Targeting key genes that play dominant roles in T cell dysfunction is an efficient strategy for cancer immunotherapy. Here, we aimed to investigate the role of TPX2 in the antitumor effect of CD8 + T cells in hepatocellular carcinoma (HCC). Flow cytometry was used to assay the level of cell surface markers and cytokines in T cells, through which we found that TPX2 was downregulated in HCC-infiltrating CD8 + T cells. TPX2 depletion restricted the antitumor activity of CD8 + T cells, and TPX2 overexpression increased the antitumor effect of CD8 + T cells in tumor-bearing Cd8−/− mice. TPX2 overexpression improved the antitumor function of human CD8 + T cells and response to anti-PD-1 therapy in an HCC patient-derived xenograft (PDX) mouse model with or without anti-PD-1 therapy. In mechanism, TPX2 promotes the phosphorylation of P65, thus increases the level of p-P65 in nuclear, and p-P65 binds to the promoter of CXCR5, activates its transcription, and increases the level of CXCR5 on CD8 + T cells in a TPX2-dependent way. In conclusion, TPX2 maintains the antitumor effect of CD8 + T cells in HCC by regulating CXCR5 via the NF-κB signaling pathway. Increased TPX2 expression in CD8 + T cells exerts synergistic effects with anti-PD-1 therapy, suggesting a promising immunotherapeutic method in HCC.