Abstract
CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) reportedly stabilizes programmed death-ligand 1 (PD-L1) and enhances the efficacy of immunotherapy. However, correlations between CMTM6 expression and the immune microenvironment and its prognostic value remain unknown in a variety of tumors. CMTM6 expression data were obtained from The Cancer Genome Atlas (TCGA) for 33 cancer types classified into high and low expression subgroups according to the median CMTM6 expression value. Pan-cancer analysis of CMTM6 protein expression in 20 tumor types was performed using a cohort from the Human Protein Atlas (HPA). PD-L1 protein expression data were obtained from The Cancer Proteome Atlas (TCPA) for 32 cancer types. Frequencies of CMTM6 copy number alterations and mutations were analyzed using cBioPortal. MANTIS was employed to estimate microsatellite instability in the TCGA cohort. CIBERSORT and the ESTIMATE algorithm were applied to estimate the relative fractions of infiltrating immune cell types and immune scores, respectively. Kaplan–Meier survival curve analysis was performed to assess the pan-cancer prognostic value of CMTM6.CMTM6 is heterogeneously expressed in diverse cancers. Further, the results revealed low CMTM6 mutation frequencies in multiple cancers. Among them, CMTM6 mutation frequency was the highest in uterine cancer. Additionally, CMTM6 expression was related to PD-L1 protein expression in breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, sarcoma (SARC), stomach adenocarcinoma, and uterine carcinosarcoma. Increased CMTM6 expression may be associated with increased infiltration of neutrophils in some types of cancer. Finally, pan-cancer analysis indicated that CMTM6 expression was closely related to overall survival in adrenocortical carcinoma, GBM, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, SARC, thymoma, and uveal melanoma. Taken together, these findings highlight that CMTM6 plays an important role in the tumor immune microenvironment, and CMTM6 has been identified to have prognostic value in some types of cancers. Thus, CMTM6 is a potential target for cancer immunotherapy and effective prognostic biomarker.
Highlights
CKLF-like MARVEL transmembrane domain-containing family (CMTM) is a novel member of the human chemokine-like factor gene superfamily, which includes CMTM 1-8 [1]
The results revealed that CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) was upregulated in six [breast invasive carcinoma (BLCA), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), kidney renal papillary cell carcinoma (KIRP), stomach adenocarcinoma (STAD), and thyroid carcinoma (THCA)] and downregulated in six [cholangiocarcinoma (CHOL), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and pheochromocytoma and paraganglioma (PCPG)] cancer types relative to that in normal tissues (Figure 1A)
High or medium CMTM6 expression levels were observed in pancreatic adenocarcinoma (PAAD) (75%), LIHC (66.7%), bladder urothelial carcinoma (BLCA) (63.6%), STAD (63.6%), ovarian serous cystadenocarcinoma (OV) (54.5%), uterine corpus endometrial carcinoma (UCEC)
Summary
CKLF-like MARVEL transmembrane domain-containing family (CMTM) is a novel member of the human chemokine-like factor gene superfamily, which includes CMTM 1-8 [1]. CMTM6 is a widely expressed protein that exists in clusters on human chromosome 3p23. It exhibits sequence homology with protein products of other family members and has a potential four-time membrane-penetrating structure. The relationship between CMTM6 and tumorigenesis has attracted increasing attention. CMTM6 expression in gliomas was previously correlated with poor prognosis, and its expression was positively correlated with inhibitory T-cell expression [2]. Joh et al reported that CMTM6 was significantly associated with longer overall survival in non-small cell lung cancer [3]. Previous studies indicate that CMTM6 plays different roles in different tumors
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