Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer

• Published in: Viruses Vol. 15; no. 9; p. 1813
• Main Authors: Nicola Candia, Alejandro J, Garcia Fallit, Matías, Peña Agudelo, Jorge A, Pérez Küper, Melanie, Gonzalez, Nazareno, Moreno Ayala, Mariela A, De Simone, Emilio, Giampaoli, Carla, Casares, Noelia, Seilicovich, Adriana, Lasarte, Juan José, Zanetti, Flavia A, Candolfi, Marianela
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 25.08.2023; MDPI
• Subjects: Adenoviruses; Breast cancer; Cell activation; Cell growth; cell penetrating peptide; Cell survival; Cell viability; chemosensitivity; Cisplatin; Cytotoxicity; ErbB-2 protein; Expression vectors; Forkhead protein; Foxp3; Foxp3 protein; Gene therapy; Health aspects; Immune system; Leukocyte migration; Lymphocytes; Lymphocytes T; Medical research; Medicine, Experimental; Metastases; Nuclear transport; Penicillin; Peptides; Physiological aspects; Transcription factors; Tumor cells; Tumors; Argentina; United States > US
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15091813

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.