CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
Open accessAbstract
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, we find that CMTM6 displays specificity for PD-L1. Notably, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo. These findings provide insights into the biology of PD-L1 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a potential therapeutic target to overcome immune evasion by tumour cells.
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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 [16]
The paper’s Abstract states that a genome-wide CRISPR/Cas9 screen identified CMTM6 and that CMTM6 protects surface PD-L1 from lysosome-mediated degradation. Our copy mentions CMTM4 only as a member of the CMTM protein family; it does not establish that the screen identified CMTM4 or that CMTM4 acts through the same mechanism. No page number is available in the indexed passages. (LLM, conf=0.88)
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 [33]
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 [16]
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- Authors
- Burr, M. L., Sparbier, C. E., Chan, Y.-C., Williamson, J. C., Woods, K., Beavis, P. A., Lam, E. Y. N., Henderson, M. A., Bell, C. C., Stolzenburg, S., Gilan, O., Bloor, S., Noori, T., Morgens, D. W., Bassik, M. C., Neeson, P. J., Behren, A., Darcy, P. K., Dawson, S.-J., Voskoboinik, I., Trapani, J. A., Cebon, J., Lehner, P. J., & Dawson, M. A.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- University of Cambridge (GB)
- La Trobe University (AU)
- Stanford University (US)
- Corresponding author
- Burr, Marian L.
- Lehner, Paul J.
- Dawson, Mark A.
- ORCID
- Burr, Marian L.
- Sparbier, Christina E.
- Chan, Yih-Chih
- Williamson, James C.
- Woods, Katherine
- Beavis, Paul A.
- Lam, Enid Y. N.
- Henderson, Melissa A.
- Bell, Charles C.
- Stolzenburg, Sabine
- Gilan, Omer
- Bloor, Stuart
- Noori, Tahereh
- Morgens, David W.
- Bassik, Michael C.
- Neeson, Paul J.
- Behren, Andreas
- Darcy, Phillip K.
- Dawson, Sarah-Jane
- Voskoboinik, Ilia
- Trapani, Joseph A.
- Cebon, Jonathan
- Lehner, Paul J.
- Dawson, Mark A.
- Venue
- Nature
- Published
- 2017-08-16
- Volume
- 549
- Issue
- 7670
- Pages
- 101-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5706633
- OpenAlex
- W2749553776
- Cited by
- 946
- References
- 19
- Citations by year
- 2026: 87 · 2025: 98 · 2024: 116 · 2023: 135 · 2022: 141 · 2021: 138 · 2020: 103 · 2019: 69 · 2018: 50 · 2017: 7 · 2015: 1
- FWCI
- 27.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Apollo
- Funders
- NHS Blood and Transplant
- Wellcome Trust (101835/Z/13/Z, 101835)
- Cancer Research UK (A20097, 20097)
- National Institute for Health and Care Research (ACF-2012-14-003)
- Cambridge Institute for Medical Research, University of Cambridge
- National Health and Medical Research Council (1106447, 1085015, 1106444)
- Cancer Council Victoria
- NIHR Cambridge Biomedical Research Centre
- National Human Genome Research Institute (T32HG000044)
- 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-L1 expression regulation, lysosomal degradation, protein recycling, recycling endosomes, plasma membrane proteome, immune checkpoint, tumor surveillance, T cell suppression, cancer immunotherapy, MHC class I, CRISPR-Cas9 screen
- MeSH terms
- Animals, Cell Line, Cell Membrane, Female, Humans, Lysosomes, Membrane Proteins, Neoplasms, Endosomes, Substrate Specificity, T-Lymphocytes, Histocompatibility Antigens Class I, Tumor Escape, Proteome, Mice, Proteolysis, B7-H1 Antigen, CRISPR-Cas Systems
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