Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer
Alejandro J. Nicola Candia,
Matías Garcia Fallit,
Jorge A. Peña Agudelo,
Melanie Pérez Küper,
Nazareno Gonzalez,
Mariela A. Moreno Ayala,
Emilio De Simone,
Carla Giampaoli,
Noelia Casares,
Adriana Seilicovich,
Juan José Lasarte,
Flavia A. Zanetti,
Marianela Candolfi
Affiliations
Alejandro J. Nicola Candia
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Matías Garcia Fallit
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Jorge A. Peña Agudelo
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Melanie Pérez Küper
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Nazareno Gonzalez
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Mariela A. Moreno Ayala
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Emilio De Simone
Cátedra de Fisiología Animal, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires C1428BFA, Argentina
Carla Giampaoli
Cátedra de Fisiología Animal, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires C1428BFA, Argentina
Noelia Casares
Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA, CUN), 31008 Pamplona, Spain
Adriana Seilicovich
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
Juan José Lasarte
Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA, CUN), 31008 Pamplona, Spain
Flavia A. Zanetti
Instituto de Ciencia y Tecnología “Dr. Cesar Milstein”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo C1440FFX, Buenos Aires, Argentina
Marianela Candolfi
Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
The regulatory T cell master transcription factor, Forkhead box P3 (Foxp3), has been detected in cancer cells; however, its role in breast tumor pathogenesis remains controversial. Here we assessed Foxp3 tumor intrinsic effects in experimental breast cancer using a Foxp3 binder peptide (P60) that impairs Foxp3 nuclear translocation. Cisplatin upregulated Foxp3 expression in HER2+ and triple-negative breast cancer (TNBC) cells. Foxp3 inhibition with P60 enhanced chemosensitivity and reduced cell survival and migration in human and murine breast tumor cells. We also developed an adenoviral vector encoding P60 (Ad.P60) that efficiently transduced breast tumor cells, reduced cell viability and migration, and improved the cytotoxic response to cisplatin. Conditioned medium from transduced breast tumor cells contained lower levels of IL-10 and improved the activation of splenic lymphocytes. Intratumoral administration of Ad.P60 in breast-tumor-bearing mice significantly reduced tumor infiltration of Tregs, delayed tumor growth, and inhibited the development of spontaneous lung metastases. Our results suggest that Foxp3 exerts protumoral intrinsic effects in breast cancer cells and that gene-therapy-mediated blockade of Foxp3 could constitute a therapeutic strategy to improve the response of these tumors to standard treatment.