title: Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing.
abstract: Missing 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.
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: María V
authors.initials: MV
authors.lastname: Martínez-Sánchez
authors.affiliation: Hematology Service, Hospital Rafael Méndez , Lorca, Murcia, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Periago
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Legaz
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gimeno
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Mrowiec
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Natividad R
authors.initials: NR
authors.lastname: Montes-Barqueros
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Campillo
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Bolarin
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: María V
authors.initials: MV
authors.lastname: Bernardo
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: María R
authors.initials: MR
authors.lastname: López-Álvarez
authors.affiliation: Hematology Service, HCUVA , Murcia, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: González
authors.affiliation: Pediatric oncology Service, HCUVA , Murcia, Spain.
authors.forename: María C
authors.initials: MC
authors.lastname: García-Garay
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muro
authors.affiliation: Hematology Service, HCUVA , Murcia, Spain.
authors.forename: Valentin
authors.initials: V
authors.lastname: Cabañas-Perianes
authors.affiliation: Hematology Service, Hospital General Universitario Santa Lucía , Cartagena, Murcia, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fuster
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: García-Alonso
authors.affiliation: Hematology Service, HCUVA , Murcia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Moraleda
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: María R
authors.initials: MR
authors.lastname: Álvarez-Lopez
authors.affiliation: Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
keywords: HLA-C; HLA-I; KIR; KIR ligands; NK cell activating receptors; NK cell licensing ; missing self; myeloma