Identification of CMTM6 and CMTM4 as PD-L1 protein regulators

By R. Mezzadra, Chong Sun, L. T. Jae, Raquel Gomez-Eerland, E. de Vries, Wei Wu, Meike E. W. Logtenberg, M. Slagter, E. Rozeman, I. Hofland and 9 more. Nature, 2017

631 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4b310f3c55ed360ef564c0ed609b5e839de8beab

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Citations in the corpus

• Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory (2019, background): “Given that PD-L1 is endocytosed from the surface of cells (Burr et al., 2017; Mezzadra et al., 2017), we hypothesized that PD-L1 is being specifically secreted in the form of exosomes.”
• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “The E3 ubiquitin ligase STUB1 (STIP1 homology and U-box containing protein 1) also polyubiquitinates PD-L1 in the cytoplasmic domain at lysine residues and downregulates PD-L1 expression, whereas CMTM6 maintains PD-L1 stability by blocking ubiquitination in tumor cells [293].”
• Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “Pre-clinical (Burr et al., 2017; Manguso et al., 2017; Mezzadra et al., 2017; Patel et al., 2017; Skoulidis et al., 2015) and clinical reports (Gao et al.”
• Mechanisms controlling PD-L1 expression in cancer (2019, background): “Moreover, CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) prevents PD-L1 from entering the recycling endosomes by blocking STUB1 and PD-L1 interaction (Burr et al., 2017; Mezzadra et al., 2017).”