Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

Abstract

Abstract Background Despite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified. Methods The expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs). Results We identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy. Conclusions Our findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC.

Keywords

• CacyBP
• Myd88
• Tumor-associated macrophage
• Programmed cell death-1
• Hepatocellular carcinoma