期刊
NATURE
卷 549, 期 7670, 页码 101-105出版社
NATURE RESEARCH
DOI: 10.1038/nature23643
关键词
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资金
- Cancer Research UK Fellowship
- Addenbrooke's Charitable Trust award
- NIHR fellowship
- Senior Leukaemia Foundation Australia Fellowship
- NHMRC [1085015, 1106444, 1106447]
- Cancer Council Victoria
- Leukaemia Foundation Australia
- Wellcome Trust PRF [101835/Z/13/Z]
- NHSBT
- NIHR Cambridge BRC
- Wellcome Trust Strategic Award
- Addenbrooke's Charitable Trust
- Wellcome Trust [101835/Z/13/Z] Funding Source: Wellcome Trust
- Cancer Research UK [20097] Funding Source: researchfish
- National Breast Cancer Foundation [PF-14-008] Funding Source: researchfish
- National Institute for Health Research [ACF-2012-14-003] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1106447, 1106444, 1085015] Funding Source: NHMRC
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance(1,2). The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression(1). 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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