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Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13085-90. doi: 10.1073/pnas.1300314110. Epub 2013 Jul 22.

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

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1
Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, and Paris Descartes University, Cochin Hospital, 75014 Paris, France.

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.

PMID:
23878221
PMCID:
PMC3740849
DOI:
10.1073/pnas.1300314110
[Indexed for MEDLINE]
Free PMC Article
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