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CCR6 activation links innate immune responses to MALT lymphoma development

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cam.depositDate2022-01-18
cam.issuedOnline2022-02-10
dc.contributor.authorDu, Ming-Qing
dc.contributor.orcidKorona, Boguslawa [0000-0001-5429-4882]
dc.date.accessioned2022-07-27T23:30:12Z
dc.date.available2022-07-27T23:30:12Z
dc.date.issued2022-06-01
dc.date.updated2022-01-18T10:43:04Z
dc.description.abstractThe genesis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by oncogenic cooperation among immunological stimulations and acquired genetic changes. We previously identified recurrent CCR6 mutations in MALT lymphoma, with majority predicted to result in truncated proteins lacking the phosphorylation motif important for receptor desensitization. Functional consequences of these mutational changes, the molecular mechanisms of CCR6 activation and how this receptor signaling contributes to MALT lymphoma development remain to be investigated. In the present study, we demonstrated that these mutations impaired CCR6 receptor internalization and were activating changes, being more potent in apoptosis resistance, malignant transformation, migration and intracellular signaling, particularly in the presence of ligands CCL20, HBD2 (human beta defensin 2) and HD5 (human alpha defensin 5). CCR6 was highly expressed in malignant B-cells irrespective of the lymphoma sites. HBD2 and CCL20 were constitutively expressed by the duct epithelial cells of salivary glands, and also those involved in lymphoepithelial lesions (LELs) in salivary gland MALT lymphoma. While in the gastric setting, HBD2, and HD5, to a less extent CCL20, were highly expressed in epithelial cells of pyloric and intestinal metaplasia respectively including those involved in LELS, which are adaptive responses to chronic H pylori infection. These findings suggest that CCR6 signaling is most likely active in MALT lymphoma, independent of its mutation status. The observations explain why the emergence of malignant B-cells and their clonal expansion in MALT lymphoma are typically around LELs, linking the innate immune responses to lymphoma genesis.
dc.description.sponsorshipthe Kay Kendall Leukemia Fund (KKL1141) UK, Blood Cancer UK (13 006), Isaac Newton Trust, Addenbrookes Charitable Trust and Department of Pathology, University of Cambridge.
dc.identifier.doi10.17863/CAM.86988
dc.identifier.eissn1592-8721
dc.identifier.issn0390-6078
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/339571
dc.language.isoeng
dc.publisherFerrata Storti Foundation
dc.publisher.departmentDepartment of Pathology
dc.publisher.urlhttp://dx.doi.org/10.3324/haematol.2021.280067
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectDefensins
dc.subjectHelicobacter Infections
dc.subjectHelicobacter pylori
dc.subjectHumans
dc.subjectImmunity, Innate
dc.subjectLymphoma, B-Cell, Marginal Zone
dc.subjectReceptors, CCR6
dc.titleCCR6 activation links innate immune responses to MALT lymphoma development
dc.typeArticle
dcterms.dateAccepted2022-01-18
prism.publicationNameHaematologica
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3324/haematol.2021.280067

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