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

• Published in: Cancer immunology, immunotherapy Vol. 61; no. 1; p. 19
• Main Authors: Mandl, Stefanie J, Rountree, Ryan B, Dalpozzo, Katie, Do, Lisa, Lombardo, John R, Schoonmaker, Peter L, Dirmeier, Ulrike, Steigerwald, Robin, Giffon, Thierry, Laus, Reiner, Delcayre, Alain
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01.01.2012
• Subjects: Breast cancer; Clinical trials; Immunotherapy; Lungs; Lymphocytes; Metastasis; Proteins; Smallpox; Tetanus; Tumors; Vaccines; Turkey; Ankara Turkey; Germany
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1077-4

MVA-BN^sup ®^-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^sup ®^-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^sub reg^) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN^sup ®^-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN^sup ®^-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8^sup +^CD11c^sup +^ T cells accompanied by a decrease in the frequency of T^sub reg^ cells in the lung, resulting in a significantly increased ratio of effector T cells to T^sub 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^sup +^ T cells or the decrease in the frequency of T^sub reg^ cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8^sup +^ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN^sup ®^-HER2. Furthermore, depletion of CD4^sup +^ or CD25^sup +^ cells demonstrated that tumor-induced T^sub reg^ cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN^sup ®^-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN^sup ®^-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression.[PUBLICATION ABSTRACT]