IL-1 -releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors

Vitale, Chiara; Ambrosini, Paolo; Montaldo, Elisa; Ballerini, Filippo; Moretta, Alessandro; Mingari, Maria Cristina

doi:10.3324/haematol.2014.110494

Cited by 14 publications

(15 citation statements)

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“…In the context of HSCT, it is possible that IL-1β released by residual AML blasts may alter the BM microenvironment and suppress the proliferation of NK cell precursors. This, in turn, could be detrimental, primarily in patients receiving haplo-HSCT in which NK cells play a fundamental role in clearing leukemia blasts surviving the conditioning regimen [71].…”

Section: Nk Cell Infiltrates Have Been Detected In Various Tumorsmentioning

confidence: 99%

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

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et al. 2015

Cancer Immunol Immunother

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It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host's defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.

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Section: Nk Cell Infiltrates Have Been Detected In Various Tumorsmentioning

confidence: 99%

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

Pietra

Vitale

Pende

et al. 2015

Cancer Immunol Immunother

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“…Indeed, conditioning regimen, presence of residual leukemia blasts, and infections could modulate ILC development. In this context, it has been shown that leukemia cells releasing the pro‐inflammatory cytokine IL‐1β influence ILC3 and NK‐cell differentiation . Moreover, in patients with acute myeloid leukemia, the frequency of ILC subsets is altered at diagnosis with a marked reduction of NCR + ILC3s .…”

Section: Introductionmentioning

confidence: 99%

The generation of human innate lymphoid cells is influenced by the source of hematopoietic stem cells and by the use of G‐CSF

et al. 2016

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NK cells play a central role in the haploidentical HSC transplantation (HSCT) to cure high-risk leukemias. Other innate lymphoid cells (ILCs Keywords: G-CSF · HSCT · ILC · ILC development · NK cells · PlerixaforAdditional supporting information may be found in the online version of this article at the publisher's web-site In the context of HSCT, NK cells play a central role in Tcell depleted HLA-haploidentical HSCT for the cure of high-risk leukemias. Indeed, alloreactive NK cells mediate graft-versusleukemia activity, contributing to the elimination of leukemia blast surviving the preparative regimen, while sparing normal tissues [6]. Moreover, before the adaptive immune response becomes fully competent, NK cells can provide protection against viral reactivation and/or primary infections [7]. Given the involvement of helper-ILCs in anti-microbial responses and in tissue remodeling, it is conceivable that, after HSCT, they may exert a protective role against chemo/radiotherapy-induced tissue damage (mucositis), development of graft-versus-host disease (GvHD), and infections. It has recently been shown that the early appearance after HSCT of donor natural cytotoxicity receptor (NCR) + ILC3 correlates with a decreased incidence of GvHD [8]. Thus, it would be important to define which conditions and factors may influence ILC differentiation. Indeed, conditioning regimen, presence of residual leukemia blasts, and infections could modulate ILC development. In this context, it has been shown that leukemia cells releasing the pro-inflammatory cytokine IL-1β influence ILC3 and NK-cell differentiation [9]. Moreover, in patients with acute myeloid leukemia, the frequency of ILC subsets is altered at diagnosis with a marked reduction of NCR + ILC3s [10]. It is conceivable that also the HSC source and the graft manipulation could influence post-transplant ILC recovery. Thus, we investigated the ILC differentiation potential of HSC isolated from BM, mobilized peripheral blood (PB), and umbilical cord blood (UCB). Results and discussion HSCs isolated from different sources display differences in the generation of NK cells and ILC3sCells isolated from BM, PB, TCR-α/β, and CD19 depleted PB (PB-α/β − 19 − ; α/βT cell and CD19 cell depleted mobilized peripheral blood), and UCB were analyzed for their phenotype after gating on CD45 + CD34 + cells (hereinafter referred to as HSC), as shown in Fig. 1A Fig. 2A-B). Notably, although the percentages of ILCs were significantly higher in BM cultures, BM HSCs displayed the lowest expansion rate (Fig. 2C). Thus, when considering the absolute numbers of CD56 + CD161 + ILCs, UCB cultures gave the highest recovery (Fig. 2D) Fig. S2A), although increasing at later time points, particularly in BM cultures (not shown). Upon stimulation, CD56 Supporting Information+ CD161 + cells produced mainly the ILC3-associated cytokines IL-22 and IL-8, while the percentages of IFN-γ-producing cells, i.e. NK cells, were low (Fig. 2H). Thus, BM and UCB HSCs display a better capability of in vitro differentiati...

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“…In that context, we observed that IL-1β, released by some AML blasts, inhibited the recovery of UCB-CD34 + -derived CD161 + CD56 + cells, leading to a reduction of LFA-1 − ILC3-like cells. Moreover, CD161 + CD56 + cells, detectable in the culture, displayed higher expression of NK receptors, perforin, and of CD107a upon incubation with AML itself [38]. Taken together, these data provide novel insight on the possible role of inflammation on NK-cell development.…”

Section: Discussionmentioning

confidence: 63%

“…In this context, we previously showed that IL-8 favors NK-cell differentiation, while IL-1β-releasing AML blasts may modulate CD161 + CD56 + cell differentiation, suggesting that inflammatory cytokines may influence such process [27,38].…”

Section: Discussionmentioning

confidence: 99%

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IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors

et al. 2015

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NK cells are innate lymphocytes characterized by the expression of nuclear factor interleukin 3 regulated (NFIL3 or E4BP4), eomesodermin (EOMES) transcription factors (TFs), and by the ability to exert cytolytic activity and release IFN-γ. In the haploidenticalhematopoietic stem cell transplantation (haplo-HSCT) setting, CD34 + donor derived NK cells play a major role in the control of leukemic relapses. Therefore, it is important to better define cytokines that influence NK-cell differentiation from CD34 + precursors. We analyzed the effects of IL-1β on NK-cell differentiation from umbilical cord blood (UCB) CD34 + cells. While IL-1β inhibited CD161 + CD56 + cell proliferation, an increased expression of LFA-1, CD94/NKG2A, KIRs, and perforin on CD56 + cells was detected. In addition, within the CD161 + CD56 + IL-1RI + LFA-1 − cell fraction (representing group 3 innate lymphoid cells, ILC3-like cells), a significant increase of EOMES, NKp46, and CD94/NKG2A receptors, cytolytic granules, and IFN-γ was detected. This increase was paralleled by a decrease of related orphan receptors (RORγt) TF, NKp44 expression, and IL-22 production. These data suggest that IL-1β inhibits ILC3-while favoring NK-cell maturation. Since in haplo-HSCT conditioning regimen, infections or residual leukemia cells may induce IL-1β production, this may influence the NK/ILC3 development from donor-derived CD34 + precursors.Keywords: IL-1β r ILC3 r Innate immunity r NK cells r NK-cell development Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural killer (NK) cells are major effectors of the innate immunity. They are able to rapidly eliminate virally infected cells or tumor cells [1][2][3]. Their activity is finely regulated by a number of activating and inhibitory receptors that tune their cytolytic Correspondence: Dr. Chiara Vitale e-mail: chiara.vitale@unige.it activity and cytokine secretion [4,5]. The main activating receptors include NKp46, NKp30, and NKp44 (collectively termed natural cytotoxicity receptors), NKG2D, and DNAM-1 [6,7]. In addition, NK cells express inhibitory receptors specific for HLA class I molecules, including killer immunoglobulin-like(Ig-like) receptors (KIRs), specific for allotypic HLA class I determinants, and * These authors contributed equally to this work as senior co-authors. Eur. J. Immunol. 2015Immunol. . 45: 2061Immunol. -2071 CD94/NKG2A specific for 9]. NK cells are characterized by production of IFN-γ and the expression of cytolytic granules. Their development requires the expression of E4BP4 (NFIL3, nuclear factor interleukin 3), Tbx21 (T-bet), eomesodermin (EOMES) transcription factor (TF) [10][11][12][13][14] and occurs primarily in the BM, proceeding through a multistep process characterized by the sequential acquisition of markers/receptors (including CD117, CD161, CD56, CD94/NKG2A, LFA-1, CD16, and KIRs) and functions [10,11,15]. NK cells are developmentally related to innate lymphoid cells (ILCs) as they derive fro...

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IL-1 -releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors

Cited by 14 publications

References 15 publications

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

The generation of human innate lymphoid cells is influenced by the source of hematopoietic stem cells and by the use of G‐CSF

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors

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IL-1 -releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors

Cited by 14 publications

References 15 publications

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

The generation of human innate lymphoid cells is influenced by the source of hematopoietic stem cells and by the use of G‐CSF

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34+ precursors

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IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors