High membrane expression of CMTM6 in hepatocellular carcinoma is associated with tumor recurrence

Abstract

CKLF‐like MARVEL transmembrane domain–containing protein 6 (CMTM6) maintains membrane PD‐L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma (HCC), the correlation among CMTM6, B7 family ligands, and CD8‐positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6‐knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki‐67 and shorter recurrence‐free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6‐knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity.

Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

“…The PD-L1 regulation effect reported initially was subsequently confirmed in monocytes (13) as well as in other species of tumor cells (14). Extensive clinical analysis also found a significant positive correlation between CMTM6 and PD-L1 expression in tumors (15)(16)(17)(18)(19)(20). Increased CMTM6 in tumors was associated with shorter overall survival (OS) and recurrence in patients with glioma, head and neck squamous cell carcinoma (HNSCC), melanoma, hepatocellular carcinoma (HCC) and triple negative breast cancer (TNBC), etc.…”

“…Increased CMTM6 in tumors was associated with shorter overall survival (OS) and recurrence in patients with glioma, head and neck squamous cell carcinoma (HNSCC), melanoma, hepatocellular carcinoma (HCC) and triple negative breast cancer (TNBC), etc. ( 18, 19, 21-24 ). Remarkably, CMTM6/PD-L1 co-expression suggested a poorer prognosis ( 20, 25-27 ), but instead a better prognosis when ICB therapies intervened ( 28-30 ).…”

CMTM6 and PD-L1 are independent prognostic biomarkers in head and neck squamous cell carcinoma

“…Also, standardization of the antibody clones, the scoring system, and the cut-off is imperative to yield homogeneous data sets. To date, no consensus on CMTM6 positivity exists, as it is mostly classi ed as "low" or "high" [35][36][37]. This leaves a source of great uncertainty for both oncologists and pathologists.…”

CMTM Family and Gastrointestinal Tract Cancers: A Comprehensive Review

“… 80 In addition, the co-expression of CMTM6/PD-L1 can regulate inflammatory cell density 77 and has a close relationship with tumor recurrence. 81 Given the participation of CMTM6 in PD-L1 stabilization, 9 , 10 combined treatment with anti-CMTM6 and anti-PD-L1 may be a new method to enhance the therapeutic benefits in HCC.…”