Centrosome protein TAX1BP2 mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in hepatocellular carcinoma

Abstract

Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type I interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity.

Keywords: Centrosome overduplication; HCC; Hepatocellular carcinoma; LKB1 activation; STING-IFN-I pathway; TAX1BP2; antitumor immunity.