CMTM6 controls PD-L1

The checkpoint ligand PD-L1 expressed by tumor cells inhibits the effector functions of CD8⁺ T cells. In Nature, Burr et al. and Mezzadra et al. identify the previously uncharacterized transmembrane protein CMTM6 as a critical regulator of the cell-surface expression of PD-L1 in cancer cells and myeloid cells in mice and humans. CMTM6 associates with both constitutive PD-L1 and interferon-γ-induced PD-L1 at the plasma membrane and in recycling endosomes. Depletion of CMTM6 does not affect transcription of the gene encoding PD-L1 or trafficking of PD-L1 from the endoplasmic reticulum to the cell surface but stabilizes cell-surface PD-L1 by preventing its lysosome-mediated degradation, possibly by preventing its ubiquitination. Depletion of CMTM6 enhances T cell activation and the anti-tumor response in vitro and in mouse melanoma models. CMTM6 shows specificity for PD-L1 and does not effect the expression of major histocompatibility complex class I or PD-L2. In addition, CMTM4 interacts with PD-L1 and restores PD-L1 expression in CMTM6-deficient melanoma cells, but other CMTM proteins do not.

Nature (16 August 2017) doi:10.1038/nature23643 and doi:10.1038/nature23669