ITGB5 promotes immune escape in hepatocellular carcinoma by regulating PD-L1 through SETDB1/Hippo signaling pathway

BACKGROUND: The overall response rate to immune checkpoint inhibitors (ICIs) in HCC patients remains low. It has been reported that ITGB5 correlate with the immune infiltration of tumors. Our previous study showed that ITGB5 reduces HCC cell sensitivity to TKIs. However, the role of ITGB5 in HCC immunity remains unclear. METHODS: The mRNA and protein expression of ITGB5, SETDB1, LATS2 and PD-L1 in hepatocellular carcinoma cells and tissues were determined by RT-qPCR, Western Blot and Immunofluorescence. PD-L1 positive cells were analyzed by flow cytometry. The relationship between ITGB5 expression and immune cell infiltration was investigated by applying TIMER database. The effects of ITGB5 on the immune response and immunotherapy of hepatocellular carcinoma were determined by constructing a spontaneous tumor model of hepatocellular carcinoma and a subcutaneous tumor model in mice. RESULTS: ITGB5 promotes immune escape in HCC by activating PD-L1 expression, a target gene of the Hippo signaling pathway, through the SETDB1-LATS2 axis. ITGB5 reduces the susceptibility of HCC to immunotherapy. Importantly, ITGB5 knockdown enhanced the efficacy of PD-1 therapy in mice harboring HCC. CONCLUSIONS: ITGB5 plays an important role in the immune response of hepatocellular carcinoma. ITGB5 may serve as a biomarker for evaluating immunotherapy efficacy and represent a promising therapeutic target for HCC treatment, either alone or in combination with anti-PD-1 antibodies.