title: Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells.
abstract: 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.
authors.affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, and Paris Descartes University, Cochin Hospital, 75014 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pommier
authors.forename: Alexandra
authors.initials: A
authors.lastname: Audemard
authors.forename: Aurélie
authors.initials: A
authors.lastname: Durand
authors.forename: Renée
authors.initials: R
authors.lastname: Lengagne
authors.forename: Arnaud
authors.initials: A
authors.lastname: Delpoux
authors.forename: Bruno
authors.initials: B
authors.lastname: Martin
authors.forename: Laetitia
authors.initials: L
authors.lastname: Douguet
authors.forename: Armelle
authors.initials: A
authors.lastname: Le Campion
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Cédric
authors.initials: C
authors.lastname: Auffray
authors.forename: Bruno
authors.initials: B
authors.lastname: Lucas
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014820:Vitiligo / Q000235:genetics / Q000276:immunology
chemical_list: D017382:Reactive Oxygen Species; D008668:Metallothionein; D051096:Proto-Oncogene Proteins c-ret