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

Abstract

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. (Hepatology Communications 2020;0:1-15).

Impact of Metabolic Activity in Hepatocellular Carcinoma: Association With Immune Status and Vascular Formation

“…The numbers of central intratumoral clusters of differentiation (CD) 8–positive lymphocytes and CD68‐positive macrophages with cytoplasmic or membrane staining in three high‐power fields were counted, as described previously. ( 9 , 13 ) The index of vessels that encapsulated tumor clusters (VETC) was calculated as reported previously. ( 9 , 14 ) Briefly, five representative fields were recorded for the total number of individual tumor clusters that were surrounded by endothelium, and the average number of endothelium‐coated tumor clusters per field is presented as the index of VETC.…”

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

“…As a key component of the TIME, TAMs play critical roles in its modulation, especially in tumor immune suppression [ 126 , 127 ]. TAMs are the most prominent immune cells in the vicinity of CAF-populated areas, suggesting tight interactions between these two cell types [ 128 ].…”

Integrated Analysis of the Expression, Prognostic Value, and Relationship with Immune Infiltration of CMTMs in Human Hepatocellular Carcinoma

“…Yugawa et al con rmed that CMTM6 and PD-L1 were coexpressed in HCC. They also found that high CMTM6 and PD-L1-positive expression was associated with malignant aggregates and shorter OS of HCC patients [44]. This may be due to its function in stabilizing PD-L1 expression, thereby facilitating escape from T-cell-mediated cytotoxicity.…”