Human NK receptors: From the molecules to the therapy of high risk leukemias

Moretta, Lorenzo; Locatelli, Franco; Pende, Daniela; Sivori, Simona; Falco, Michela; Bottino, Cristina; Mingari, Maria Cristina; Moretta, Alessandro

doi:10.1016/j.febslet.2011.04.061

Cited by 35 publications

(38 citation statements)

References 62 publications

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“…They circulate in peripheral blood and peripheral tissues, and may be more abundantly recovered in secondary lymphoid organs and in some non-lymphoid organs (e.g., the liver). They are characterized by considerable cytotoxic activity, which is due to the constitutive expression of perforin and granzyme, which may be promptly released upon cell triggering (1, 2). In addition to this unique feature, which contributes to the high efficiency with which NK cells are suited to kill virally infected or tumor cells, their function also includes the production of cytokines, such as IFN-γ, tumor necrosis factor (TNFα) and G-CSF, and the early release of chemokines (MIP-1a/b, RANTES) (3).…”

Section: Introductionmentioning

confidence: 99%

“…NK cell function is finely regulated by the interplay of a wide array of activating and inhibitory receptors expressed on their surface (1). The accurate regulation of this signaling system guarantees that under baseline conditions their exceptional ability to rapidly kill is harnessed by inhibitory receptors mostly (but not exclusively, e.g., Siglec7 and IRP60) specific for “self” MHC class I molecules (2), which turn NK cells “off” and normally prevent NK-mediated lysis of HLA class I + autologous cells.…”

Section: Introductionmentioning

confidence: 99%

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Baseline and Dynamic Expression of Activating NK Cell Receptors in the Control of Chronic Viral Infections: The Paradigm of HIV-1 and HCV

et al. 2014

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Natural killer (NK) cell function is regulated by a balance between the triggering of activating and inhibitory receptors expressed on their surface. A relevant effort has been focused so far on the study of KIR carriage/expression setting the basis for NK cell education and self-tolerance. Focus on the evolution and regulation of activating NK receptors has lagged behind so far. Our understanding of activating receptor expression and regulation has recently improved by evidences derived from in vitro and in vivo studies. Virus infection – either acute or chronic – determines preferential expansion of NK cells with specific phenotype, activating receptors, and with recall-like functional activity. Studies on patients with viral infection (HIV and HCV) and specific diverging clinical courses confirm that inter-individual differences may exist in baseline expression of natural cytotoxicity receptors (NKp46 and NKp30). The findings that patients with divergent clinical courses have different kinetics of activating receptor density expression upon NK cell activation in vitro provide an additional, time-dependent, functional parameter. Kinetic changes in receptor expression thus represent an additional parameter to basal receptor density expression. Different expression and inducibilities of activating receptors on NK cells contribute to the high diversity of NK cell populations and may help our understanding of the inter-individual differences in innate responses that underlie divergent disease courses.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Baseline and Dynamic Expression of Activating NK Cell Receptors in the Control of Chronic Viral Infections: The Paradigm of HIV-1 and HCV

et al. 2014

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“…On a per cell basis, NK cells might represent optimal candidates for the cure of neoplastic patients and adoptive immunotherapy with NK cells is a novel promising treatment strategy (1)(2)(3)(4). In vivo, however, the tumor microenvironment could affect NK cell recruitment and activation, steps that are essential for the development of effective antitumor responses.…”

Section: H Uman Nk Cells Represent Important Effectors Against Hematomentioning

confidence: 99%

Neuroblastoma-Derived TGF-β1 Modulates the Chemokine Receptor Repertoire of Human Resting NK Cells

Castriconi

Dondero

Bellora

et al. 2013

The Journal of Immunology

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In this study, we show that neuroblastoma (NB) cell conditioning affects the chemokine receptor repertoire of human resting NK cells. In particular, NB cells upregulated the expression of CXCR4 and CXCR3 in all NK cells and downregulated CX3CR1 in the CD56dim subset. On the contrary, the expression of CXCR1 and CCR7 remained unaltered. The phenomenon was dependent on the release by NB cells of TGF-β1, and rTGF-β1 induced a chemokine receptor repertoire identical to that of NB-conditioned NK cells. The immune modulatory role of TGF-β1 appears to be dose dependent because low amounts of the cytokine were sufficient to modulate CXCR4 and CX3CR1 expression, intermediate amounts modified that of CXCR3, and high amounts were necessary to downregulate the expression of the NKp30 activating receptor. Notably, a similar receptor modulation was observed in rTGF-β2–conditioned NK cells. Finally, the analysis of NK cells from patients with stage 4 NB suggests that NB conditioning could exert in vivo an immune modulatory effect resembling that emerged from in vitro experiments. Altogether our data propose a novel tumor escape-mechanism based on the modulation of chemokine receptors that play pivotal roles in NK cells bone marrow homing, egress, or recruitment into peripheral tissues.

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“…Natural killer (NK) cells are appealing candidates for cancer immunotherapy [10,11]. Mounting evidence demonstrates that peripheral blood NK cells, once activated, promote Th1-type immune responses and exert potent cytolytic activity against tumor cells of different histotypes.…”

Section: Introductionmentioning

confidence: 99%

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

et al. 2014

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We analyzed the functional outcome of the interaction between tumor-associated macrophages (TAMs) and natural killer (NK) cells. TAMs from ascites of ovarian cancer patients displayed an alternatively activated functional phenotype (M2) characterized by a remarkably high frequency and surface density of membrane-bound IL-18. Upon TLR engagement, TAMs acquired a classically activated functional phenotype (M1), released immunostimulatory cytokines (IL-12, soluble IL-18), and efficiently triggered the cytolytic activity of NK cells. TAMs also induced the release of IFN-γ from NK cells, which however was significantly lower compared with that induced by in vitro-polarized M2 cells. Most tumor-associated NK cells displayed a CD56 bright , CD16 neg or CD56 bright , CD16 dim phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire. Importantly however, when appropriately stimulated, NK cells from the patients, including those cells isolated from ascites, efficiently killed autologous TAMs that expressed low, "nonprotective" levels of HLA class I molecules. Overall, our data show the existence of a complex tumor microenvironment in which poorly cytolytic/immature NK cells deal with immunosuppressive tumor-educated macrophages.Keywords: Human r Natural killer cells r Ovarian cancer r Tumor-associated macrophages Additional supporting information may be found in the online version of this article at the publisher's web-site [3][4][5][6]. Tumor and stromal cells produce chemokines such as CCL2 that recruit monocytes from peripheral blood. Once in tissue, the tumor microenvironment would prevent their differentiation into DCs while promoting differentiation into macrophages. Moreover, it would skew the macrophage polarization toward a proangiogenic/immunoregulatory M2-like phenotype with tumor-promoting properties. Notably, most studies have established a correlation between high numbers of tumorassociated macrophages (TAMs) within a tumor and poor prognosis [7][8][9]. Thus, an attractive novel clinical approach could be to identify factors able to revert TAMs into macrophages with M1 tumor-suppressive properties.Other innovative therapeutic protocols aim at increasing the function of immune effector cells with antitumor capabilities. Natural killer (NK) cells are appealing candidates for cancer immunotherapy [10,11] Results TAMs express high amounts of mIL-18TAMs were purified from ascitic fluids of patients affected by ovarian carcinoma (Table 1) and analyzed by flow cytometry for the expression of a large panel of cell surface markers ( Fig. 1 and Supporting Information Fig. 1). The results were compared with those obtained using in vitro IL-4-polarized M2 cells derived from peripheral blood monocytes of healthy donors. According to the gene expression profile analyses [19,20], the surface phenotype of TAMs closely resembled that of M2 cells (S...

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Human NK receptors: From the molecules to the therapy of high risk leukemias

Cited by 35 publications

References 62 publications

Baseline and Dynamic Expression of Activating NK Cell Receptors in the Control of Chronic Viral Infections: The Paradigm of HIV-1 and HCV

Baseline and Dynamic Expression of Activating NK Cell Receptors in the Control of Chronic Viral Infections: The Paradigm of HIV-1 and HCV

Neuroblastoma-Derived TGF-β1 Modulates the Chemokine Receptor Repertoire of Human Resting NK Cells

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

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