杀伤细胞免疫球蛋白样受体（KIR）抑制性配体（HLA-I）的过表达决定了骨髓瘤的免疫监视依赖于多样且强大的自然杀伤（NK）细胞致敏。
Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing.
作者信息
Martínez-Sánchez María V, Periago Adela, Legaz Isabel, Gimeno Lourdes, Mrowiec Anna, Montes-Barqueros Natividad R, Campillo José A, Bolarin José M, Bernardo María V, López-Álvarez María R, González Consuelo, García-Garay María C, Muro Manuel, Cabañas-Perianes Valentin, Fuster Jose L, García-Alonso Ana M, Moraleda José M, Álvarez-Lopez María R, Minguela Alfredo
机构信息
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.
Hematology Service, Hospital Rafael Méndez , Lorca, Murcia, Spain.
出版信息
Oncoimmunology. 2015 Oct 29;5(4):e1093721. doi: 10.1080/2162402X.2015.1093721. eCollection 2016 Apr.
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 KIR2DL1L2L3 genotypes (2.8% vs. 13.2%, < 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 (KIR2DL1L2L3/C2C2, 2.56% vs. 0.35%; < 0.05; OR = 15.014), single-KIR2DL3/C1 (20.51% vs. 10.84%; < 0.05; OR = 2.795) and single-KIR2DL2/C1 (12.82% vs. 4.9%; < 0.01; OR = 5.18) interactions were over-represented in myeloma, compared to controls. Additionally, KIR2DL1L2L3 (20% vs. 83%, < 0.00001) as well as KIR3DL1 (23% vs. 82%, < 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. KIR2DL1L2L3/C2C2 patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myeloma-PCs (4% vs. 15%; < 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.
缺失自我识别使癌症对自然杀伤细胞（NKc）反应敏感。然而，该模型忽略了NKc的许可效应，即抑制性杀伤细胞免疫球蛋白样受体（iKIR）与其同源HLA-I配体相互作用会显著增强NKc反应。在164例白种人患者和286例对照中评估了iKIR/HLA配体（HLA-C1/C2）许可相互作用对浆细胞（PC）发育异常易感性和进展的影响。与对照组相比，骨髓瘤患者中KIR2DL1L2L3基因型的积累（2.8%对13.2%，<0.01，OR=5.29）以及NKc克隆的外周库多样性较低。iKIR2D/HLA-C许可相互作用的多样性较低且亲和力较弱的库增加了骨髓瘤的易感性。因此，与对照组相比，骨髓瘤患者中完全缺乏传统的iKIR2D/HLA-C许可相互作用（KIR2DL1L2L3/C2C2，2.56%对0.35%；<0.05；OR=15.014）、单KIR2DL3/C1（20.51%对10.84%；<0.05；OR=2.795）和单KIR2DL2/C1（12.82%对4.9%；<0.01；OR=5.18）相互作用的比例过高。此外，KIR2DL1L2L3（20%对83%，<0.00001）以及KIR3DL1（23%对82%，<0.00001）基因型对3年无进展生存期（PFS）有显著负面影响，尤其是在肿瘤负荷较低的患者中。值得注意的是，与K562和其他血液系统癌症相比，骨髓瘤PC显示出HLA-I（“增加自我”而非缺失自我）包括HLA-C的大量过表达，以及NKc激活受体（aRec）CD112、CD155、ULBP-1和MICA/B配体的轻度表达，这显然使骨髓瘤PC主要易被获得许可的NKc裂解。KIR2DL1L2L3/C2C2患者（无传统的iKIR2D/HLA-C许可相互作用）能裂解K562，但几乎不能裂解骨髓瘤PC（4%对15%；与对照组相比，<0.05）。这些结果支持了一种模型，即对非缺失自我的癌症（如骨髓瘤）的免疫监视主要依赖于NKc许可。
Zotero 插件