Identification of CMTM6 and CMTM4 as PD-L1 protein regulators

CMTM6 and CMTM4 bind to and stabilize the inhibitory receptor PD-L1 and regulate PD-L1 levels at the surface of human tumour and immune cells. PD-1/PD-L1 blocking antibodies are effective in the treatment of various cancers. In this study, Ton Schumacher and colleagues describe a haploid genetic screen to identify molecules and pathways that influence the cell surface expression of PD-L1. They identify chemokine-like factors CMTM6 and CMTM4 as cell endogenous regulators of PD-L1 stability, and suggest that this axis could be targeted therapeutically to improve cancer immunotherapy. Elsewhere in this issue, Mark Dawson and colleagues also identify CMTM6 as a novel regulator of PD-L1 expression, through a genome-wide CRISPR–Cas9 screen. CMTM6 functions to maintain PD-L1 at the plasma membrane by inhibiting its lysosome-mediated degradation and promoting its recycling. The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses1,2,3,4,5,6,7,8,9. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited10,11,12,13,14,15. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.