Identification of CMTM6 and CMTM4 as PD-L1 protein regulators.

Abstract

The clinical benefit in patients with diverse types of metastatic cancers that is observed upon blockade of the PD-1 – PD-L1 interaction has highlighted the importance of this inhibitory axis in the suppression of tumor-specific T cell responses1–9. In spite of the key role of PD-L1 expression by cells within the tumor micro-environment, our understanding of the regulation of the PD-L1 protein is limited10–15. Using a haploid genetic screen, we here identify 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 tumor 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 all other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 transcript 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, T cell inhibitory capacity of PD-L1 expressing tumor cells is enhanced by CMTM6. 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.