Therapeutic blockade of Foxp3 in experimental breast cancer models

Purpose Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function. Methods Mice bearing established syngeneic LM3 and 4T1...

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Bibliographic Details
Published in:	Breast cancer research and treatment 2017-11, Vol.166 (2), p.393-405
Main Authors:	Moreno Ayala, Mariela A., Gottardo, María Florencia, Imsen, Mercedes, Asad, Antonela S., Bal de Kier Joffé, Elisa, Casares, Noelia, Lasarte, Juan José, Seilicovich, Adriana, Candolfi, Marianela
Format:	Article
Language:	eng
Subjects:	Analysis Animal models Animals Antitumor activity Breast cancer Breast Neoplasms - immunology Breast Neoplasms - metabolism Breast Neoplasms - therapy Cancer Cancer immunotherapy Cancer research Cancer treatment Cancer vaccines Cancer Vaccines - administration & dosage Cancer Vaccines - pharmacology Care and treatment Cell Line, Tumor Cell-Penetrating Peptides - administration & dosage Cell-Penetrating Peptides - pharmacology Dendritic cells Dendritic Cells - immunology Dendritic Cells - transplantation Female Forkhead Transcription Factors - antagonists & inhibitors Foxp3 protein Health aspects Humans Immunoregulation Immunosuppression Immunotherapy Interleukin 10 Lymphocytes T Medicine Medicine & Public Health Mice Oncology Peptides Preclinical Study T cells T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology Treatment Outcome Tumor cells Tumor Microenvironment - drug effects Tumors Vaccines Xenograft Model Antitumor Assays
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Summary:	Purpose Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function. Methods Mice bearing established syngeneic LM3 and 4T1 breast tumors were treated with antitumor DC vaccines and a synthetic peptide (P60) that has been shown to inhibit Foxp3. Results Treatment with P60 improved the therapeutic efficacy of DC vaccines in these experimental models. In addition, monotherapy with P60 inhibited tumor growth in immunocompetent as well as in immuno-compromised animals bearing established tumors. We found expression of Foxp3 in human and murine breast tumor cells. P60 inhibited IL-10 secretion in breast cancer cells that expressed Foxp3. Conclusions Our results suggest that Foxp3 blockade improves the therapeutic efficacy of DC vaccines by inhibition of Tregs and through a direct antitumor effect. This strategy could prove useful to neutralize the immunosuppressive microenvironment and to boost antitumor immunity in breast cancer.
ISSN:	0167-6806 1573-7217