Related Experiment Video
Updated: Nov 21, 2025
Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with
Sandra Martinez-Morilla1, Jon Zugazagoitia1, Pok Fai Wong1
1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract:
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) modulates degradation of a number of proteins, including programmed death ligand-1 (PD-L1) by protecting it from ubiquitin-mediated degradation. In this role, it could modulate the effectiveness of immunotherapy. Here, for the first time, we characterize CMTM6 expression in melanoma and evaluate its association with response to immune checkpoint inhibitors (ICI). We evaluated the expression of CMTM6, PD-L1 and other immune-related proteins in 60 pretreatment biopsies from metastatic melanoma patients who received immunotherapy, in a tissue microarray (TMA) using quantitative immunofluorescence (QIF). Expression of mRNA from control patients obtained from The Cancer Genome Atlas (TCGA) database was also compared. CMTM6 expression was positively correlated with PD-L1, CD3, CD20, and CD68 markers, at protein (Pearson's r = 0.53-0.81, all P < .0001) and mRNA (Spearman's r = 0.15-0.44, all P < .002, except for CD68 where P = .26) levels. CMTM6 protein was associated with longer survival after immunotherapy when measured in the stromal (P = .007) and all the immune compartments tested (T cells, B cells, and macrophages). Multivariable analyses also revealed significant CMTM6 survival associations when measured in stromal (Hazard Ratio (HR) = 0.12, P = .001) and CD68-positive (HR = 0.30, P = .043) compartments. Additionally, PD-L1 but not CMTM6 showed prognostic value in control patients. Finally, high CMTM6 and PD-L1 co-expression in the stromal compartment was significantly associated with longer survival in treated patients (P = .028). Consequently, CMTM6 expression shows potential as a predictive factor for ICI treatments.
Insights
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) protein levels correlate with better outcomes in melanoma patients treated with immune checkpoint inhibitors (ICI). High CMTM6 and PD-L1 co-expression predicts longer survival, suggesting CMTM6 as a potential biomarker for immunotherapy response.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) regulates protein degradation, including programmed death ligand-1 (PD-L1).
- PD-L1 is a key target in immune checkpoint inhibitor (ICI) therapy for cancers like melanoma.
- The role of CMTM6 in melanoma and its impact on ICI treatment response remain largely uncharacterized.
Purpose of the Study:
- To characterize CMTM6 expression in melanoma.
- To evaluate the association between CMTM6 expression and response to ICI therapy.
- To assess CMTM6 as a potential predictive biomarker for immunotherapy.
Main Methods:
- Quantitative immunofluorescence (QIF) was used to assess CMTM6, PD-L1, and immune cell markers in pretreatment melanoma biopsies (n=60).
- Gene expression data from The Cancer Genome Atlas (TCGA) was used for comparative mRNA analysis.
- Survival analyses, including multivariable models, were performed to correlate CMTM6 expression with patient outcomes.
Main Results:
- CMTM6 protein and mRNA expression positively correlated with PD-L1, CD3, CD20, and CD68.
- Higher CMTM6 protein levels in stromal and immune cell compartments were associated with significantly longer survival after ICI therapy.
- Co-expression of CMTM6 and PD-L1 in the stroma was linked to improved survival in treated patients.
Conclusions:
- CMTM6 expression is associated with immune infiltration and PD-L1 levels in melanoma.
- CMTM6 serves as a significant predictive biomarker for improved survival in patients receiving ICI treatment.
- Targeting or understanding CMTM6 could enhance the efficacy of melanoma immunotherapy.
