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Strategies to sensitize hepatocellular carcinomas (HCC) to programmed death-1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitor therapies are important in improving the survival of HCC patients. The aim of the study was to characterize C-X-C chemokine receptor 2 (Cxcr2) as a therapeutic target in HCC and evaluate the effects of Cxcr2 suppression in sensitizing HCC to PD1/PD-L1 inhibitor therapies. To this end, we constructed a Cxcr2-knockout HCC cell line (Hepa1-6 KO) using the CRISPR-Cas9 approach and assessed the tumor growth rate and survival of mice after subcutaneously inoculating Hepa1-6 KO cells in mice. We show that Cxcr2 knockdown does not dramatically inhibit tumor growth and improve mouse survival. In tumor xenografts, the proportion of T cells is not affected but the ratio of M1/M2 macrophage is greatly increased. Cxcr2 knockdown does not alter cell viability but macrophages co-cultured with Hepa1-6 KO cells are shifted to M1 phenotypes compared to WT cells. Hepa-1-6 KO cells exhibit lower levels of PD-L1 expression. c-Myc is suppressed in Hepa1-6 KO cells, which contributes to PD-L1 downregulation. Knockdown of Cxcr2 decreases PD-L1 levels and consequently promotes the shift of macrophages to the M1 phenotype, which is mediated by downregulating c-Myc. In summary, Cxcr2 is a potential target for suppressing immune escape in HCC.

C-X-C chemokine receptor 2 (Cxcr2) promotes hepatocellular carcinoma immune evasion via regulating programmed death-ligand 1 (PD-L1)