Chemokines play an important role in tumor pathologenesis, autoimmune diseases and other processes, and provide new targets for treatment. CMTM family, consisting of 8 members (CMTM 1–8, previously known as human chemokine-like factor superfamily (CKLFSF))[6], plays an important role in tumorigenesis and development [7–8]. In this study, we investigated the immunohistochemical expression of one of the CMTM family members CMTM6 in a large series of cervical squamous cell carcinomas. We also investigated PD-L1, which is regulated by CMTM6 in these tumors. We found that CMTM6 and PD-L1 was expressed in 81.6% and 78.9% cervical squamous cell carcinomas, respectively. A positive correlation between the expression of CMTM6 and PD-L1 was also observed these tumors. CMTM6 expression was correlated with perineural invasion and lymph node status whereas PD-L1 expression was correlated with tumor differentiation.
CMTM6 is a widely expressed protein involved in epigenetic regulation, embryonic development and tumorigenesis. Studies had found that CMTM6 can act as a key regulator of PD-L1 in tumor cells, bind to PD-L1 and maintain its expression on the cell surface. CMTM6 coexists with PD-L1 in cells, CMTM6 can prevent PD-L1 from becoming a target of lysosome-mediated degradation. CMTM6 gene knockout only causes the reduction of PD-L1 protein on the cell surface, but does not reduce the level of PD-L1mRNA, so CMTM6 can regulate the level of PD-L1 at the protein level[10, 11]. The reduction of PD-L1 expression level significantly reduces the effect of inhibiting tumor-specific T cell activity[14]. CMTM6 shows obvious specificity in preventing PD-L1 from being degraded, and does not express antigen through MHC class I molecules. This suggests that CMTM6 can be used as a potential therapeutic target and enhance anti-tumor immunity to a certain extent[15].
In non-small cell lung cancer and oral squamous cell carcinoma, a positive correlation between CMTM6 protein level and PD-L1 protein level was observed [16, 17]. Our research results show there was a positive correlation between the expression of CMTM6 and PD-L1 in cervical squamous cell carcinoma. In hepatocellular carcinoma, the level of CMTM6 protein is significantly lower than that of adjacent tissues. In addition, the level of CMTM6 protein is related to pathological grade, tumor metastasis and AFP level in hepatocellular carcinoma [18]. Inn breast carcinoma, the expression level of CMTM6 is significantly higher than that of adjacent normal breast tissue, and is related to pathological stage and positive HER2 expression [19]. However, we found that the expression of CMTM6 in cervical cancer was significantly higher than that in normal cervical squamous mucosa. In our cervical squamous carcinomas, CMTM6 expression is associated with lymph node metastasis and nerve invasion. There was no relationship between CMTM6 expression and other clinicopathological features of cervical cancer patients. PD-L1 is only related to the degree of tumor differentiation. The above results indicate that CMTM6 has different expression levels in different tumors and different prognostic significance.