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Immunosurveillance of Erbb2 Carcinogenesis in Transgenic Mice Is Concealed by a Dominant Regulatory T-Cell Self-Tolerance

¹ Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy; ² CeSI, Aging Research Center, "G. D'Annunzio" University Foundation, Chieti, Italy; ³ Molecular Biotechnology Center, University of Turin, Torino, Italy; and ⁴ Karmanos Cancer Institute, Wayne State University, Detroit, Michigan

Requests for reprints: Federica Cavallo, Department of Clinical and Biological Sciences, University of Turin, Ospedale San Luigi Gonzaga, I-10043 Orbassano, Italy. Phone: 39-11-790-5419; Fax: 39-11-236-5417; E-mail: federica.cavallo{at}unito.it.

To assess the role of CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cells in overcoming immunosurveillance of Erbb2 (HER-2/neu) mammary lesions, we studied the effects of their sustained removal in BALB/c female mice made transgenic for the rat Erbb2 (r-Erbb2) oncogene (BALB-neuT mice), which develop multiple mammary carcinomas. During the progression of these lesions, Treg cells expand in the spleen, tumor draining lymph nodes, and tumors. Repeated administration of anti-CD25 antibodies extends tumor-free survival, reduces carcinoma multiplicity, and leads to the manifestation of a natural antibody and CTL-mediated reactivity against r-Erbb2. Loss of Foxp3⁺ Treg cells during anti-CD25 treatment remarkably caused the disappearance of Gr1⁺ immature myeloid cells, suggesting a cross-talk between these two inhibitory immune cell types. Treg cell expansion associated with r-Erbb2 overexpression may be seen as a physiologic response to dampen the immune reaction elicited by local anomalous overexpression of a self-antigen. (Cancer Res 2006; 66(15): 7734-40)

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