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Open Access 01-01-2012 | Original Article

Immunotherapy with MVA-BN^®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

Authors: Stefanie J. Mandl, Ryan B. Rountree, Katie Dalpozzo, Lisa Do, John R. Lombardo, Peter L. Schoonmaker, Ulrike Dirmeier, Robin Steigerwald, Thierry Giffon, Reiner Laus, Alain Delcayre

Published in: Cancer Immunology, Immunotherapy | Issue 1/2012

Abstract

MVA-BN^®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN^®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (T_reg) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN^®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN^®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8⁺CD11c⁺ T cells accompanied by a decrease in the frequency of T_reg cells in the lung, resulting in a significantly increased ratio of effector T cells to T_reg cells. In contrast, administration of HER2 protein formulated in Complete Freund’s Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8⁺ T cells or the decrease in the frequency of T_reg cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8⁺ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN^®-HER2. Furthermore, depletion of CD4⁺ or CD25⁺ cells demonstrated that tumor-induced T_reg cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN^®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN^®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression.

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Title: Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells
Authors: Stefanie J. Mandl
Ryan B. Rountree
Katie Dalpozzo
Lisa Do
John R. Lombardo
Peter L. Schoonmaker
Ulrike Dirmeier
Robin Steigerwald
Thierry Giffon
Reiner Laus
Alain Delcayre
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 1/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1077-4

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