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Spontaneous Vitiligo in an Animal Model for Human Melanoma

Role of Tumor-specific CD8⁺ T Cells

¹ Département d’Immunologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Laboratoire membre de l’IFR 116, Université R. Descartes, Paris, France; ² Laboratory of Tumor Immunology, Division of Oncology, Geneva, Switzerland; ³ Unité de Recherche et d’Expertise en Histotechnologie et Pathologie, Institut Pasteur, Paris, France; ⁴ Department of Immunology, Nagoya University School of Medicine, Nagoya, Japan; ⁵ UPR 9021 CNRS, Strasbourg, France; and ⁶ INSERM CRI/IFR69, Hopital P. Brousse, Villejuif, France

Tumor antigen-reactive T cells can be detected in a large proportion of melanoma patients, but their efficacy on tumor control in vivo remains unclear. On the other hand, vitiligo, a skin disorder characterized by patchy depigmented macules, may occur spontaneously or after antitumor therapies. Moreover, vitiligo is significantly associated with positive clinical response, but the mechanism is not understood. Therefore, the establishment of a relevant animal model in which melanoma and vitiligo spontaneously develop stepwise may be useful for better understanding of the parameters involved in the destruction of both benign and malignant melanocytes. In a previous work, we established a mouse model for melanoma in which MT/ret transgenic mice express the ret oncogene fused to the metallothionein promoter. Here we report that melanoma leads to spontaneous vitiligo. We further investigate, for the first time in this model, the natural antitumor T-cell response and evaluate the role of cellular immunity in the development of the disease. Interestingly, the occurrence of spontaneous tumor nodules in MT/ret mice with melanoma-associated vitiligo is significantly delayed when compared in melanoma mice without vitiligo. Moreover, a significant proportion of mice with melanoma-associated vitiligo resisted a challenge with syngeneic melanoma cells in contrast to animals without vitiligo. Our results confirm that vitiligo is associated with clinical benefit and further demonstrate the crucial role of CD8⁺ T cells for tumor control in melanoma-associated vitiligo.

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