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Assaying Surface Expression of Chemosensory Receptors in Heterologous Cells
Published on: February 23, 2011
CMTM6 suppresses cell-surface expression of death receptor FAS in mice but not in humans
Tereza Semberova1, Michaela Pribikova1, Veronika Cimermanova2,3
1Laboratory of Immunity & Cell Communication, Division BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
Abstract:
The transmembrane protein CMTM6 promotes plasma membrane expression of the immune checkpoint protein PD-L1, a key suppressor of anti-tumor immunity. Targeting CMTM6 has been proposed as a strategy to enhance tumor cell killing by reducing PD-L1 surface expression. In accord, ablation of CMTM6 in mouse cancer models was shown to efficiently suppress tumor growth, but unexpectedly in a manner partially independent of PD-L1, suggesting that CMTM6 may regulate additional proteins involved in anti-tumor immunity. Using mass spectrometry, we discovered that mouse CMTM6 strongly associates with the cell death receptor FAS and negatively regulates its surface expression in mice. Deletion of CMTM6 increases FAS plasma membrane localization and sensitizes murine cells to FAS ligand-induced cytotoxicity. However, the interaction between CMTM6 and FAS is absent in human cells due to the difference in three amino acids at the boundary of the FAS extracellular and transmembrane domains. Altogether, our findings urge caution when translating promising data regarding the targeting of CMTM6 from mouse cancer models to potential human therapies.
Insights
Targeting CMTM6 may enhance anti-tumor immunity by reducing PD-L1. However, CMTM6 also regulates FAS, a cell death receptor, but this interaction is absent in humans, cautioning against direct translation of mouse cancer model findings.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Cell Biology
Background:
- CMTM6 promotes PD-L1 expression, a suppressor of anti-tumor immunity.
- Targeting CMTM6 is a proposed strategy to enhance anti-cancer immunity.
- Mouse models show CMTM6 ablation suppresses tumor growth, partly independent of PD-L1.
Purpose of the Study:
- Investigate additional targets of CMTM6 beyond PD-L1.
- Determine if CMTM6 regulates other proteins involved in anti-tumor immunity.
- Assess the translational potential of CMTM6 targeting from mouse models to human therapies.
Main Methods:
- Mass spectrometry to identify CMTM6 interacting proteins.
- Analysis of CMTM6's effect on FAS surface expression in mouse cells.
- Comparison of CMTM6-FAS interaction in mouse and human cells.
Main Results:
- Mouse CMTM6 associates with the cell death receptor FAS.
- CMTM6 deletion increases FAS surface expression and sensitizes cells to FAS ligand-induced cytotoxicity.
- The CMTM6-FAS interaction is absent in human cells due to sequence differences.
Conclusions:
- CMTM6 regulates FAS-mediated cytotoxicity in mice, independent of PD-L1.
- Differences in the FAS protein sequence between mice and humans limit direct translation of CMTM6 targeting strategies.
- Caution is advised when extrapolating CMTM6 targeting data from mouse cancer models to human therapies.
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