Morgan, Huw J;
Rees, Elise;
Lanfredini, Simone;
Powell, Kate A;
Gore, Jasmine;
Gibbs, Alex;
Lovatt, Charlotte;
... Patel, Girish K; + view all
(2022)
CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis.
Journal of Clinical Investigation
, 132
(21)
, Article e150750. 10.1172/JCI150750.
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Abstract
The basis of immune evasion, a hallmark of cancer, can differ even when cancers arise from one cell type such as in the human skin keratinocyte carcinomas: basal and squamous cell carcinoma. Here we showed that the basal cell carcinoma tumor–initiating cell surface protein CD200, through ectodomain shedding, was responsible for the near absence of NK cells within the basal cell carcinoma tumor microenvironment. In situ, CD200 underwent ectodomain shedding by metalloproteinases MMP3 and MMP11, which released biologically active soluble CD200 into the basal cell carcinoma microenvironment. CD200 bound its cognate receptor on NK cells to suppress MAPK pathway signaling that in turn blocked indirect (IFN-γ release) and direct cell killing. In addition, reduced ERK phosphorylation relinquished negative regulation of PPARγ-regulated gene transcription and led to membrane accumulation of the Fas/FADD death receptor and its ligand, FasL, which resulted in activation-induced apoptosis. Blocking CD200 inhibition of MAPK or PPARγ signaling restored NK cell survival and tumor cell killing, with relevance to many cancer types. Our results thus uncover a paradigm for CD200 as a potentially novel and targetable NK cell–specific immune checkpoint, which is responsible for NK cell–associated poor outcomes in many cancers.
| Type: | Article |
|---|---|
| Title: | CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI150750 |
| Publisher version: | https://doi.org/10.1172/JCI150750 |
| Language: | English |
| Additional information: | Copyright: © 2022, Morgan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, ACTIVATED-RECEPTOR-GAMMA, DOWN-REGULATION, CUTANEOUS NEOPLASMS, INITIATING CELLS, HAIR FOLLICLE, SOLUBLE CD200, SKIN CANCERS, STEM-CELLS, T-CELLS, CARCINOMA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165175 |
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