Histone deacetylase 2 regulates STAT1-dependent upregulation of atypical chemokine receptor 3 to induce M2 macrophage migration and immune escape in hepatocellular carcinoma

Abstract

Atypical chemokine receptor 3 (ACKR3) has been linked to the tumor microenvironment. This work investigates the effects of ACKR3 and its regulatory molecules on the chemotactic migration of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC). RT-qPCR and western blot assays identified elevated ACKR3 and HDAC2 levels in HCC tissues and cells. Knockdown or overexpression of ACKR3 was induced in HCC cells through vectors of lentivirus plasmids, and then the conditioned medium of the HCC cells was collected to stimulate TAMs. The stimulated TAMs were co-cultured with CD3+ T cells. ACKR3 knockdown in HCC cells inhibited migration of TAMs and promoted M1 polarization, which restored the activity of T cells. Histone deacetylase 2 (HDAC2) recruited signal transducer and activator of transcription 1 (STAT1) to the ACKR3 promoter to activate ACKR3 transcription. HDAC2 silencing suppressed nuclear translocation of STAT1 and decreased ACKR3 expression. HDAC2 knockdown in HCC cells similarly suppressed TAM migration, promoted M1 polarization, and restored T cell function, but these changes were inversed by ACKR3 upregulation. HDAC2 or ACKR3 silencing weakened tumor growth and immune escape in mice. In conclusion, this study demonstrates that HDAC2 upregulates ACKR3 via STAT1 to induce migration of M2 macrophages and immune escape in HCC.