Identification of CMTM6 and CMTM4 as PD-L1 protein regulators
Open accessAbstract
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.
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CMTM6 and CMTM4 stabilize PD-L1 surface expression by preventing lysosome-mediated degradation.
“a genome-wide CRISPR screen identified two previously uncharacterized regulators, CMTM6 and CMTM4, which stabilize PD-L1 surface expression by preventing lysosome-mediated degradation [16,17].”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [17]
The main text (indexed as Abstract; page unavailable) identifies CMTM6 and CMTM4 as regulators of PD-L1 stability and proposes that CMTM6 protects surface PD-L1 from degradation. It does not identify that degradation as lysosome-mediated. It also describes haploid genetic screens, not a genome-wide CRISPR screen; the Methods describe CRISPR/Cas9 for generating knockout cell lines. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSeveral critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability.
“Moreover, several critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability31–36.”
From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [31]
Among the eight genes whose perturbation shifted PD-L1 protein levels, five were positive regulators (PD-L1 downregulation upon perturbation) and three were negative regulators.
“We identified five positive regulators (PD-L1 downregulation upon perturbation) and three negative regulators, a subset of which had been previously validated [9,11,13,16,17,29].”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [17]
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“Moreover, several critical proteins including CMTM4, CMTM6, GSK3 β , CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability 31 – 36 .”
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- Authors
- Mezzadra, R., Sun, C., Jae, L. T., Gomez-Eerland, R., de Vries, E., Wu, W., Logtenberg, M. E. W., Slagter, M., Rozeman, E. A., Hofland, I., Broeks, A., Horlings, H. M., Wessels, L. F. A., Blank, C. U., Xiao, Y., Heck, A. J. R., Borst, J., Brummelkamp, T. R., & Schumacher, T. N. M.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Utrecht University (NL)
- Austrian Academy of Sciences (AT)
- Corresponding author
- Brummelkamp, Thijn R.
- Schumacher, Ton N. M.
- ORCID
- Venue
- Nature
- Published
- 2017-08-16
- Volume
- 549
- Issue
- 7670
- Pages
- 106-110
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6333292
- OpenAlex
- W2745732448
- Cited by
- 697
- References
- 33
- Citations by year
- 2026: 40 · 2025: 64 · 2024: 78 · 2023: 99 · 2022: 105 · 2021: 109 · 2020: 91 · 2019: 57 · 2018: 45 · 2017: 8 · 2015: 1
- FWCI
- 24.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Cancer Research Institute
- Koninklijke Nederlandse Akademie van Wetenschappen
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.Vici.170.033)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CMTM6, PD-L1, PD-1/PD-L1 axis, protein stability, ubiquitination, lysosomal degradation, protein recycling, cell surface expression, tumor immune evasion, cancer immunotherapy, dendritic cells, tumor microenvironment, metastatic cancer
- MeSH terms
- Dendritic Cells, Genetic Complementation Test, Haploidy, Humans, Melanoma, Protein Binding, Cell Line, Tumor, Ubiquitination, Protein Stability, B7-H1 Antigen, MARVEL Domain-Containing Proteins, CRISPR-Cas Systems
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