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CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis

Morgan, Huw J., Rees, Elise, Lanfredini, Simone ORCID:, Powell, Kate A., Gore, Jasmine, Gibbs, Alex, Lovatt, Charlotte, Davies, Gemma E., Olivero, Carlotta ORCID:, Shorning, Boris Y., Tornillo, Giusy, Tonks, Alex ORCID:, Darley, Richard ORCID:, Wang, Eddie C.Y. ORCID: and Patel, Girish K. 2022. CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis. Journal of Clinical Investigation 132 (21) , e150750. 10.1172/JCI150750

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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 (gamma interferon release) and direct cell killing. In addition, reduced ERK phosphorylation relinquished negative regulation of PPARγ regulated gene transcription and lead to membrane accumulation of the Fas/FADD death receptor and its ligand, FasL that 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: American Society for Clinical Investigation
ISSN: 1558-8238
Date of First Compliant Deposit: 14 September 2022
Date of Acceptance: 1 September 2022
Last Modified: 07 Jan 2024 03:25

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