Spontaneous Vitiligo in an Animal Model for Human Melanoma

Lengagne, Renée; Gal, Frédérique-Anne Le; Garcette, Marylène; Fiette, Laurence; Avé, Patrick; Kato, Masashi; Briand, Jean‐Paul; Massot, Christian; Nakashima, Izumi; Rénia, Laurent; Guillet, Jean‐Gérard; Prévost-Blondel, Armelle

doi:10.1158/0008-5472.can-03-2828

Cited by 54 publications

(56 citation statements)

References 31 publications

(69 reference statements)

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“…1A). As described previously (14), mice with vitiligo displayed less cutaneous metastases than mice without vitiligo. Next, we compared, by flow cytometry (SI Appendix, Figs.…”

Section: Decreased Incidence Of Cutaneous Metastases In Mt/ret Mice Dsupporting

confidence: 66%

“…In this model, the primary uveal tumor disseminates early but remains dormant for several weeks (12,13). MT/ret mice then develop cutaneous metastases and finally distant (i.e., pulmonary, visceral, and mediastinal adenopathy) metastases (14). A significant proportion of MT/ret mice spontaneously develops vitiligo-like depigmentations.…”

mentioning

confidence: 99%

“…A significant proportion of MT/ret mice spontaneously develops vitiligo-like depigmentations. The tumor progression is significantly delayed in mice harboring vitiligo compared with mice without depigmented skin (14). The development of vitiligo in melanoma patients has also been associated with a better prognosis (15)(16)(17)(18).…”

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confidence: 99%

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Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Pommier

Audemard

Durand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4 + T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4 + T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.T he concept of suppressive T cells, which was first described in the early 1970s, remained poorly investigated until Sakaguchi et al. demonstrated the suppressive functions of a subset of CD4 + T cells now called regulatory T cells (Tregs) (1). Tregs express Foxp3 (2) and high surface levels of the α-chain of the IL-2 receptor (CD25) and are the main mediators of peripheral tolerance under physiological settings (1). Their role in the suppression of antitumor immunity was originally described in the 1980s (3) but remained, at first, largely underestimated. The demonstration that systemic depletion of Tregs favors tumor rejection in mouse models highlighted their contribution in tumor progression (4). Whereas it is established that Tregs potently interfere with tumorspecific T cells (5-8), their impact on innate immune cells, in particular, on myeloid cells, has been clearly less investigated in the context of tumor development (9, 10).To decipher the role of Tregs in the relationship between cancer immunity and autoimmunity, we used mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice) (11). In this model, the primary uveal tumor disseminates early but remains dormant for several weeks (12, 13). MT/ret mice then develop cutaneous metastases and finally distant (i.e., pulmonary, visceral, and mediastinal adenopathy) metastases (14). A significant proportion of MT/ret mice spontaneously develops vitiligo-like depigmentations. The tumor progression is significantly delayed in mice harboring vitiligo compared with mice without depigmented skin (14). The development of vitiligo in melanoma patients has...

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“…1A). As described previously (14), mice with vitiligo displayed less cutaneous metastases than mice without vitiligo. Next, we compared, by flow cytometry (SI Appendix, Figs.…”

Section: Decreased Incidence Of Cutaneous Metastases In Mt/ret Mice Dsupporting

confidence: 66%

mentioning

confidence: 99%

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Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Pommier

Audemard

Durand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…[12][13][14] To address the role of NOS2 in the tumor development, we set up a new Ret model in which NOS2 is genetically inactivated (RetNos2KO mice). 50% of RetNos2KO mice developed a primary melanoma at day 67, whereas the median time for tumor detection in Ret mice was day 38 (Fig.…”

Section: Nos2 Deficiency Delays Tumor Cell Dissemination In Melanomamentioning

confidence: 99%

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

et al. 2016

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ABSTRACTgd T lymphocytes may exert either protective or tumor-promoting functions in cancer, mostly based on their polarization toward interferon (IFN)-g or interleukin (IL)-17 productions, respectively. Here, we demonstrate that gd T cells accelerate the spontaneous metastatic melanoma development in a model of transgenic mice for the human RET oncogene (Ret mice). We identify unanticipated roles of inducible nitric oxide synthase (NOS2) in favoring the recruitment of pro-tumor gd T cells within the primary tumor. gd T cells isolated from Ret mice deficient for NOS2 produced more IFNg and less IL-17 than their counterparts from Ret mice. By supporting IL-17 production by gd T cells, NOS2 leads to the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and metastasis formation. NOS2 also reduces the cytotoxicity of gd T cells toward melanoma cells. Finally, we detected NOS2 expressing gd T cells in the primary tumor and tumor-draining lymph nodes in Ret mice, but also in human melanoma. Overall our results support that this NOS2 autocrine expression is responsible for the polarization of gd T cells toward a pro-tumor profile.

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“…Using ret transgenic mouse model of spontaneous melanoma that mimics human melanoma with respect to tumor growth, metastatic profile, histopathology and expression of melanoma associated antigens [88][89][90], we have studied the frequencies and activities of Gr1 + CD11b + MDSCs in melanoma lesions [48]. It has been found a remarkable accumulation of MDSCs in skin tumors and metastatic lymph nodes that significantly correlated with the tumor progression.…”

Section: General Characteristic Of Mdscsmentioning

confidence: 99%

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

Umansky

Sevko

2012

Cancer Microenvironment

116

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Tumor progression has been demonstrated to be supported by chronic inflammatory conditions developed in the tumor microenvironment and characterized by the longterm secretion of various inflammatory soluble factors (including cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) and strong leukocyte infiltration. Among leukocytes infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only strongly inhibit an anti-tumor immune reactions mediated by T cells but also directly stimulate tumorigenesis, tumor growth and metastasis by enhancing neoangiogenesis and creating a suitable environment for the metastatic formation. This review provides an overview of interactions between MDSCs and tumor cells leading to MDSC generation, activation and migration to the tumor site, where they can strongly enhance tumor progression. Better understanding of the MDSC-tumor interplay is critical for the development of new strategies of tumor immunotherapy.

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Spontaneous Vitiligo in an Animal Model for Human Melanoma

Cited by 54 publications

References 31 publications

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

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Spontaneous Vitiligo in an Animal Model for Human Melanoma

Cited by 54 publications

References 31 publications

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

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Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells