Abstract：
: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 responses. 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 limited. 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.
journal_name
Naturejournal_title
Natureauthors
Mezzadra R,Sun C,Jae LT,Gomez-Eerland R,de Vries E,Wu W,Logtenberg MEW,Slagter M,Rozeman EA,Hofland I,Broeks A,Horlings HM,Wessels LFA,Blank CU,Xiao Y,Heck AJR,Borst J,Brummelkamp TR,Schumacher TNMdoi
10.1038/nature23669subject
Has Abstractpub_date
2017-09-07 00:00:00pages
106-110issue
7670eissn
0028-0836issn
1476-4687pii
nature23669journal_volume
549pub_type
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