CMTM6 suppresses cell-surface expression of death receptor FAS in mice but not in humans

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.