Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: Implications for tumor evasion of T and NK cells

Bernal, Mónica; Garrido, Pilar; Jiménez, Pilar; Carretero, Rafael; Almagro, Manuel; López, Pilar; Navarro, Pilar; Garrido, Federico; Ruiz‐Cabello, Francisco

doi:10.1016/j.humimm.2009.07.004

Cited by 48 publications

(38 citation statements)

References 15 publications

(18 reference statements)

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“…38 Certainly, our data and others. 27 demonstrate that myeloma-PCs, compared to normal lymphocytes and other hematological cancers, showed increased expression of HLA-I ("increasing self"), including HLA-C, and mild expression of ligands for NK cell C and L1 C S1 C (e), and KIR2DL2/S2 C and L3 C (f) subsets were set in appropriate dotplots. 35 These gates were logically combined to assigned KIR2D expression to CD3 …”

Section: Discussionmentioning

confidence: 99%

“…23,24 With respect to this, it has been described that myeloma cells express ligands for NK cell activating receptors, 25,26 but only scarce and contradictory results concerning the expression of inhibitory ligands (HLA-I). 27,26,28 are available. Plasma cell dyscrasias (PCDs) are a group of diseases characterized by the proliferation of clonal PCs and the presence of monoclonal gammopathy.…”

Section: Introductionmentioning

confidence: 99%

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

Martínez‐Sánchez¹,

Periago

Legáz³

et al. 2015

OncoImmunology

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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 lowtumor 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. KIR2DL1patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myelomaPCs (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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Martínez‐Sánchez¹,

Periago

Legáz³

et al. 2015

OncoImmunology

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“…By binding the corresponding ligands, the activating receptors trigger NK cell-mediated target cell lysis. Thus, NK cell activation and killing of tumors is tightly regulated by processes involving the integration of signals delivered from multiple activating and inhibitory receptors (Lanier 2005;Bryceson et al 2006;Bernal et al 2009). …”

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confidence: 99%

Identification and Functional Analysis of Ligands for Natural Killer Cell Activating Receptors in Colon Carcinoma

Zhang

et al. 2012

Tohoku J. Exp. Med.

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Natural killer (NK) cells play important roles in the immune defense against tumor cells. The function of NK cells is determined by a balance between activating and inhibitory signals. DNAX accessory molecule-1 (DNAM-1) and NK group 2 member D (NKG2D) are major NK cell activating receptors, which transduce activating signals after binding their ligands CD155, CD112 and major histocompatibility complex class I-related chains A and B (MICA/B). However, the expression and functions of these ligands in colon carcinoma are still elusive. Here, we show the higher expression of CD155, CD112 and MICA/B in colon carcinoma tissues, although no correlations between the ligands expression and patient clinicopathological parameters were found. The subsequent cytotoxicity assay indicated that NK cells effectively kill colon carcinoma cells. Functional blocking of these ligands and/or receptors with antibodies led to significant inhibition of NK cell cytotoxicity. Importantly, expression of DNAM-1 and NKG2D was reduced in NK cells of colon cancer patients, and this reduction could directly suppress the activation of NK cells. Moreover, colon cancer patients have higher serum concentrations of sCD155 and sMICA/B (soluble ligands, secreted or shed from cells) than those in healthy donors (sCD155, 127.82 ± 44.12 vs. 63.67 ± 22.30 ng/ml; sMICA, 331.51 ± 65.23 vs. 246.74 ± 20.76 pg/ml; and sMICB, 349.42 ± 81.69 vs. 52.61 ± 17.56 pg/ml). The upregulation of these soluble ligands may down-regulate DNAM-1 and NKG2D on NK cells, ultimately leading to the inhibition of NK cytotoxicity. Colon cancer might be a promising target for NK cell-based adoptive immunotherapy.

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“…Accordingly, NK cells have been regarded as promising vectors for the treatment of HLA class I-negative cancers (39). It is thought that tumor cells compensate for HLA class I loss by favoring the expression of additional NK-inactivating ligands and by losing antagonist ligands with NK-activating properties (40). Expression of HLA-G, an NK cell inhibitory ligand, was previously associated with a worse prognosis in colorectal cancer (41).…”

Section: Discussionmentioning

confidence: 99%

“…Several molecules have been proposed to be characteristic for NK cells or, at least, expressed by certain NK cell subsets (40). Our investigation included CD56, NKp46, and CD16, among others.…”

Section: Discussionmentioning

confidence: 99%

Infiltration of Lynch Colorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

Miranda

Goudkade

Jordanova

et al. 2012

Clinical Cancer Research

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Purpose: Lynch syndrome colorectal cancers often lose human leukocyte antigen (HLA) class I expression. The outgrowth of clones with immune evasive phenotypes is thought to be positively selected by the action of cytotoxic T cells that target HLA class I-positive cancer cells. To investigate this hypothesis, we related the type and density of tumor lymphocytic infiltrate in Lynch colorectal cancers with their HLA class I phenotype and clinicopathologic stage.Experimental Design: HLA class I expression was assessed by means of immunohistochemistry. Characterization of tumor-infiltrating lymphocytes was carried out by using a triple immunofluorescence procedure that allowed the simultaneous detection of CD3-, CD8-, and granzyme B (GZMB)-positive cells. Additional markers were also used for further characterization of an elusive CD3Results: We discovered that high tumor infiltration by activated CD8 þ T cells correlated with aberrant HLA class I expression and associated with early tumor stages (P < 0.05). CD8 þ T cells were most abundant in HLA class I heterogeneous tumors (P ¼ 0.02) and frequent in HLA class I-negative cases (P ¼ 0.04) when compared with HLA class I-positive carcinomas. An elusive immune cell population (was characteristic for HLA class I-negative tumors lacking lymph node metastases (P < 0.01). Conclusions:The immune system assumes an important role in counteracting the progression of Lynch colorectal cancers and in selecting abnormal HLA class I phenotypes. Our findings support the development of clinical strategies that explore the natural antitumor immune responses occurring in Lynch syndrome carriers.

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Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: Implications for tumor evasion of T and NK cells

Cited by 48 publications

References 15 publications

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

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

Identification and Functional Analysis of Ligands for Natural Killer Cell Activating Receptors in Colon Carcinoma

Infiltration of Lynch Colorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

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