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Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

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dc.contributor.authorMartínez Sánchez, María V.
dc.contributor.authorPeriago, Adela
dc.contributor.authorMrowiec, Anna
dc.contributor.authorMontes Baqueros, Natividad R.
dc.contributor.authorCampillo, Jose Antonio
dc.contributor.authorBolarin, José M.
dc.contributor.authorBernardo, María V.
dc.contributor.authorLópez Álvarez, María R.
dc.contributor.authorGonzález, Consuelo
dc.contributor.authorGarcía Caray, María C.
dc.contributor.authorMuro, Manuel
dc.contributor.authorCabañas Perianes, Valentín
dc.contributor.authorFuster, Jose L.
dc.contributor.authorGarcía Alonso, Ana M.
dc.contributor.authorMoraleda, José M.
dc.contributor.authorÁlvarez López, María Rocio
dc.contributor.authorMinguela, Alfredo
dc.contributor.authorGimeno Arias, Lourdes
dc.contributor.authorLegaz Pérez, Isabel
dc.contributor.departmentCiencias Sociosanitarias
dc.date.accessioned2024-07-12T07:57:58Z
dc.date.available2024-07-12T07:57:58Z
dc.date.issued2016-04-08
dc.description© 2016 Taylor & Francis Group, LLC. This manuscript version is made available under the CC-BY-NC 4.0 license http://creativecommons.org/licenses/by-nc/4.0/. This document is the Published version of a Published Work that appeared in final form in OncoImmunology. To access the final edited and published work see https://doi.org/10.1080/2162402X.2015.1093721
dc.description.abstractMissing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands. The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls. Compared to controls, myeloma accumulates KIR2DL1−L2+L3− genotypes (2.8% vs. 13.2%, p < 0.01, OR = 5.29) and less diverse peripheral repertoires of NKc clones. Less diverse and weaker-affinity repertoires of iKIR2D/HLA-C licensing interactions increased myeloma susceptibility. Thus, the complete absence of conventional iKIR2D/HLA-C licensing interactions (KIR2DL1−L2+L3−/C2C2, 2.56% vs. 0.35%; p < 0.05; OR = 15.014), single-KIR2DL3+/C1+ (20.51% vs. 10.84%; p < 0.05; OR = 2.795) and single-KIR2DL2+/C1+ (12.82% vs. 4.9%; p < 0.01; OR = 5.18) interactions were over-represented in myeloma, compared to controls. Additionally, KIR2DL1−L2+L3− (20% vs. 83%, p < 0.00001) as well as KIR3DL1− (23% vs. 82%, p < 0.00001) genotypes had a dramatic negative impact on the 3-y progression-free survival (PFS), particularly in patients with low-tumor burden. Remarkably, myeloma-PCs, compared to K562 and other hematological cancers, showed substantial over-expression of HLA-I (“increasing-self” instead of missing-self), including HLA-C, and mild expression of ligands for NKc activating receptors (aRec) CD112, CD155, ULBP-1 and MICA/B, which apparently renders myeloma-PCs susceptible to lysis mainly by licensed NKc. KIR2DL1−L2+L3−/C2C2 patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myeloma-PCs (4% vs. 15%; p < 0.05, compared to controls). These results support a model where immunosurveillance of no-missing-self cancers, e.g., myeloma, mainly depends on NKc licensing.es
dc.formatapplication/pdfes
dc.format.extent12es
dc.identifier.citationOncoinmmunology 2016, Vol.5, n.4
dc.identifier.doihttps://doi.org/10.1080/2162402X.2015.1093721
dc.identifier.issnPrint: 2162-4011
dc.identifier.issnElectronic: 2162-402X
dc.identifier.urihttp://hdl.handle.net/10201/143023
dc.languageenges
dc.publisherTaylor and Francis Group
dc.relationThis work was supported by excellence project of Seneca (GERM/06/2008), CajaMurcia Foundations, Instituto de Salud Carlos III (ISCiii) Project FISPI13/02297 (co-financed with FEDER funds) and Association Pablo Ugarte (APU). Isabel Legaz was financed by the Sara Borrell Program from the Fondo de Investigaci on Sanitaria del ISCiii, Ministerio de Economia y Competitividad, Spain. Lourdes Gimeno was supported by ISCiii (CA09/00099). M. Roc ıo L opez-Alvarez was supported by Seneca Foundation (04087/GERM/06 Project), Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD) and Programa Nacional de Movilidad de Recursos Humanos, Plan Nacional de I-DCi 2008–2011, Ministerio de Educacion. Mar ıa V. Mart ınez-S anchez was supported by APU. A.M. designed research, analyzed data and wrote the paper; M.R.A-L. guided the interpretation of the immunological data. A.P. coordinated collection of clinical data and helped with clinical interpretation of data; M.V.M-S., I.L., L.G., N.R.M. and A.Mrowiec performed exper imental analysis; J.A.C., M.V.B., M.R.L-A., A.M.G-A. and M.M. contributed to the immunological interpretation of data; C.G., M.C.G-G, V.C-P. J.L.F. and J.M.M. coordinated the enrolment of patients and con trols; J.M.B. helped with statistical analysees
dc.relation.publisherversionhttps://www.tandfonline.com/doi/full/10.1080/2162402X.2015.1093721
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAtribución-NoComercial 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/*
dc.subjectHLA-Ces
dc.subjectHLA-Ies
dc.subjectKIRes
dc.subjectKIR ligandses
dc.titleOverexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensinges
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
relation.isAuthorOfPublicationa0170301-b64f-46f8-810a-ff18c9bf0a5f
relation.isAuthorOfPublicationb83b4b59-2d61-40f0-9108-5c6a6d158295
relation.isAuthorOfPublication.latestForDiscoverya0170301-b64f-46f8-810a-ff18c9bf0a5f
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