CMTM6 Stabilizes PD‐L1 Expression and Is a New Prognostic Impact Factor in Hepatocellular Carcinoma

CKLF‐like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a regulator of programmed death ligand 1 (PD‐L1), which induces antitumor immunity in several cancers. This study aimed to clarify the relationship between CMTM6 and PD‐L1 expression and clinical outcomes in patients with hepatocellular carcinoma (HCC). In total, 259 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for CMTM6 and PD‐L1 was performed. The relationships between CMTM6 expression and the clinicopathological characteristics and outcomes were analyzed. Additionally, the stabilization of PD‐L1 expression and regulation of malignant activities by CMTM6 were examined in vitro. Our patients were divided into high (n = 65, 25.1%) and low (n = 194, 74.9%) CMTM6 expression groups. High CMTM6 expression was significantly associated with malignant aggregates, including poor differentiation (P < 0.0001), microscopic intrahepatic metastasis (P = 0.0369), and multiple intrahepatic recurrences (P = 0.0211). CMTM6 expression was significantly correlated with PD‐L1 expression in HCC tissues (P < 0.0001). The patients were classified into three groups: high CMTM6/PD‐L1 positive (n = 21), high CMTM6/ PD‐L1 negative (n = 44), and low CMTM6 (n = 194) expression pattern groups. Overall survival was significantly different among the three groups (P < 0.0001). Additionally, immunohistochemical double staining revealed that CMTM6 and PD‐L1 were co‐expressed on HCC cells. In vitro, PD‐L1 expression was enhanced at late time points in the presence of CMTM6 expression. CMTM6 also regulated epithelial‐to‐mesenchymal transition and stemness phenotypes in HCC cells. Conclusion: Our large cohort study found that CMTM6 co‐expressed with PD‐L1 was strongly associated with the clinical outcome in patients with HCC. The evaluation of CMTM6 combined with PD‐L1 in HCC might be useful for patient selection in immune checkpoint therapy.