<scp>W</scp>iskott–<scp>A</scp>ldrich syndrome protein deficiency in natural killer and dendritic cells affects antitumor immunity

Catucci, Marco; Zanoni, Ivan; Drăghici, Elena; Bosticardo, Marita; Castiello, Maria Carmina; Venturini, Massimo; Cesana, Daniela; Montini, Eugenio; Ponzoni, Maurilio; Granucci, Francesca; Villa, Anna

doi:10.1002/eji.201343935

Cited by 25 publications

(30 citation statements)

References 22 publications

(31 reference statements)

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“…It has previously been shown that WASp − mice bred to tumor susceptible Cdkn2a knockout background also show earlier death and poor rejection of injected B16 melanoma cells when compared to WASp + mice. 30 Poor tumor survival and rejection capacity is at least partly caused by reduced tumor surveillance by WASp − NK cells and cytotoxic T cells as we and others have shown. 30-34 It is therefore likely that poor tumor prognosis in p53 +/- WASp − could be explained by aberrant tumor surveillance by WASp − cytotoxic cells.…”

Section: Discussionmentioning

confidence: 81%

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model

et al. 2018

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The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To understand the role of WASp in tumorigenesis, we bred WASp+, WASp−, and WASp-XLN mice onto tumor susceptible p53+/- background and sub-lethally irradiated them to enhance tumor development. We followed the cohorts for 24 weeks and tumors were characterized by histology and flow cytometry to define the tumor incidence, onset, and cell origin. We found that p53+/-WASp+ mice developed malignancies, including solid tumors and T cell lymphomas with 71.4% of survival 24 weeks after irradiation. p53+/-WASp− mice showed lower survival rate and developed various early onset malignancies. Surprisingly, the p53+/-WASp-XLN mice developed malignancy mostly with late onset, which caused delayed mortality in this colony. This study provides evidence for that loss-of-function and gain-of-function mutations in WASp influence tumor incidence and onset.

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Section: Discussionmentioning

confidence: 81%

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model

et al. 2018

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“…Moreover, DCs from WAS patients show defects in phagocytosis [29,30] and in their ability to form podosomes and lamellipodia, resulting in defective migratory responses [31,32] and therefore also contribute to the effect. Although in the study by Catucci et al, the numbers of splenic DCs were comparable in LPS-treated Was −/− and WT mice [11], the impaired DC migration toward SLOs and the incomplete redistribution to T-cell areas that has previously been observed in studies involving Was −/− DCs [31] might also contribute to the defect in tumor immunosurveillance.…”

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confidence: 76%

“…This link between WAS and increased cancer incidence has been explored by Catucci et al [11] in the present issue of the European Journal of Immunology. In order to test the hypothesis that Was deficiency affects tumor immunosurveillance in vivo, the authors crossed Was −/− mice to Cdkn2a −/− mice.…”

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confidence: 82%

“…DC-NK cell crosstalk can take place both in secondary lymphoid organs (SLOs) as well as in nonlymphoid peripheral sites of inflammation [23]. Although it still remains to be determined the location at which the relevant DC-NK cell interactions occur in their system, Catucci et al demonstrate that Was −/− DCs failed to induce IFN-γ by WT NK cells upon in vitro and in vivo activation with LPS [11]. In contrast to these data, it was previously shown that conjugate formation by human NK cells and WAS-silenced DCs results in as much IFN-γ production from NK cells as with WT DCs [27].…”

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confidence: 99%

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NK/DC crosstalk in immunosurveillance: A broken relationship caused by WASP‐deficiency

Romagnani

Babić

2014

Eur J Immunol

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Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency, which is characterized by abnormal immune system functions caused by the lack of expression of WAS protein (WASp). A higher tumor susceptibility is observed in WAS patients; whether this is a direct consequence of impaired immunosurveillance due to WAS deficiency in immune cells is, however, an open question. In this issue of theWiskott-Aldrich syndrome (WAS) or its less severe forms, such as X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN), are caused by the lack of expression of WAS protein (WASp) or its expressed but nonfunctional form, respectively. Both clinical forms are primarily a result of the mutations in the WAS gene. WASp is a 502-amino acid intracellular protein that is exclusively expressed in cells of the hematopoietic system [1]. Together with ubiquitously expressed neural (N)-WASp and SCAR (suppressor of cAMP receptor)/WAVE (WASp-family verprolin homology protein), WASp forms a distinct family of proteins, which are involved in cell signaling and cytoskeletal reorganization. In a steady state, WASp exists in an autoinhibited form, and its activation is dependent on the activity of WIP (WASp interacting protein), Cdc42 (Cell division control protein 42) and PIP2 (phosphatidylinositol biphosphate), upon which the C-terminus of Correspondence: Dr. Chiara Romagnani e-mail: romagnani@drfz.de WASp binds to and activates the Arp2/3 (actin-related proteins) complex [2]. The Arp2/3 complex stimulates actin polymerization by creating a new nucleation core, which is an initial step in the formation of actin filaments [3] and important for processes, such as cell motility, phagocytosis, and the formation of the immunological synapse (IS . The mechanisms underlying this phenomenon could be multiple. In Fig. 1, we try to envisage at which steps Was deficiency could impact on NK-cell-mediated tumor immunosurveillance. These effects might at least partially depend on the inability of NK cells derived from Was −/− mice to form a lytic IS with the tumor cells (Fig. 1). Moreover, WASp has also been implied in regulating the stop signal resulting after the interaction between the NK-cell activating receptor NKG2D and its ligands on the target cells [21]. However, this may only be part of the story since it was shown that the control of B16 cell-derived melanoma depends on IFN-γ produced by NK cells rather than on perforin expression [22]. Although NK cells can produce IFN-γ directly after the interaction with a tumor cell and although T-cell cytokine secretion depends on WASp, the requirements for NK-cell IFN-γ release at the synapse are not well understood [16]. It should be remembered that NK-cell IFN-γ production is also induced by IL-12 and IL-18 derived from mature DCs. Furthermore, mature DCs secrete type I IFN, which enhances the cytotoxic function of NK cells and also mediates NK-cell survival and proliferation through IL-15 transpresentation [23]. Thus, crosstalk with DCs is crucial for NK-cell priming and activation and has also ...

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“…Cellular factors that foster NK-DC crosstalk has emerged to be critical in the regulation of antitumor responses. Gene silencing or gene deficiency of WAS protein in DC impaired NK-DC conjugate formation, impaired NK activation, enhanced tumor growth and enhanced metastasis of melanoma cells [36,37]. Enhanced tumor incidence and onsets of B16 melanoma and methylcholanthrene-induced fibrosarcoma were observed in the conditional knockout mice in which IL-27 was specifically deleted in DC [38].…”

Section: Enhancing Nk-dc Crosstalk In Cancer Immunotherapymentioning

confidence: 99%

Bidirectional Interactions of NK Cells and Dendritic Cells in Immunotherapy: Current and Future Perspective

et al. 2015

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NK cells and dendritic cells (DC) are innate cellular components that regulate adaptive immune responses in the immune surveillance of cancer and infections. Interactions of NK and DC are bidirectional. In this mini review, we summarized how NK cells regulate immature DC editing and maturation, how DC regulate NK-cell functions reciprocally in the NK-DC crosstalk, and the importance of NK-DC crosstalk in antitumor immunity. Enhancing NK-DC crosstalk by cellular factor(s), antibodies or creating a microenvironment that promote NK activations, DC maturation and NK-DC crosstalk will provide new insights into future development of DC-based immunotherapy.

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Wiskott–Aldrich syndrome protein deficiency in natural killer and dendritic cells affects antitumor immunity

Abstract: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by reduced or absent expression of the WAS protein (WASP). WAS patients

Cited by 25 publications

References 22 publications

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model

NK/DC crosstalk in immunosurveillance: A broken relationship caused by WASP‐deficiency

Bidirectional Interactions of NK Cells and Dendritic Cells in Immunotherapy: Current and Future Perspective

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Wiskott–Aldrich syndrome protein deficiency in natural killer and dendritic cells affects antitumor immunity

Abstract: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by reduced or absent expression of the WAS protein (WASP). WAS patients

Cited by 25 publications

References 22 publications

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53±murine model

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53±murine model

NK/DC crosstalk in immunosurveillance: A broken relationship caused by WASP‐deficiency

Bidirectional Interactions of NK Cells and Dendritic Cells in Immunotherapy: Current and Future Perspective

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Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^±murine model