Draber, P.; Semberova, T.; Pribikova, M.; Kissiova, H.; Trivic, T.; Stepanek, O.

The transmembrane protein CMTM6 was shown to promote plasma membrane expression of immune checkpoint PD-L1, an important suppressor of anti-tumor immunity. Targeting of CMTM6 was proposed as a strategy to decrease surface PD-L1 and trigger cytotoxicity against tumors. In accord, ablation of CMTM6 in mouse cancer models was shown to efficiently suppress tumor growth in a manner partially independent of PD-L1, which suggested that CMTM6 might regulate other 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 expression in mice. Deletion of CMTM6 promotes FAS membrane localization and renders murine cells sensitive to FASL-mediated cytotoxicity. However, the interaction between CMTM6 and FAS is lost in human cells due to the difference in three amino acids at the boundary of the FAS extracellular and transmembrane domains. Altogether, our data urge caution when transferring promising data regarding the targeting of CMTM6 from mouse cancer models to potential human therapies.