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.
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We thank F. Scheeren, E. Stickel, V. Blomen, M. Brockmann and the other members of the Schumacher and Brummelkamp laboratories for discussions, J. Grabowska for technical assistance, K. Kemper and D. Peeper for sharing melanoma PDX models and the NKI- AVL flow facility, the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and/or laboratory support. This work was supported by The Queen Wilhelmina Cancer Research Award and European Research Council (ERC) Advanced Grant SENSIT (to T.N.M.S.), NWO Vici Grant (016.Vici.170.033), the Cancer Genomics Center (CGC.nl), and Ammodo KNAW Award 2015 for Biomedical Sciences (to T.R.B.), The Cancer Research Institute (CRI) Irvington Postdoctoral Fellowship (to C.S.), The Landsteiner Foundation for Blood Research, grant 1355 (to J.B.), Proteins@Work, a program of the Netherlands Proteomics Centre financed by NWO, the Netherlands Organisation for Scientific Research (to A.J.R.H.) and The Institute for Chemical Immunology, an NWO Gravitation project (to T.N.M.S. and A.J.R.H.).
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