The small molecule TGF-ß signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.
Cancer Immunol Immunother
; 61(4): 511-21, 2012 Apr.
Article
em En
| MEDLINE
| ID: mdl-21971588
ABSTRACT
Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine TGF-ß, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion, and survival of activated T cells. In this study, we examined the therapeutic efficacy and anti-tumor immune response induced by the combination of a small molecule TGF-ß signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-ß-secreting 4T1 mammary tumor model. Our data show that SM16 and anti-OX40 mutually enhanced each other to elicit a potent anti-tumor effect against established primary tumors, with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules, and a cure rate of 38%. This positive treatment outcome was associated with a 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+ and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells suggests that the anti-tumor efficacy of SM16+ anti-OX40 therapy is T cell dependent. Mice that were cured of their tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response. Taken together, these data suggest that combining a TGF-ß signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Fator de Crescimento Transformador beta
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Compostos Azabicíclicos
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Imunoterapia
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Neoplasias Mamárias Experimentais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cancer Immunol Immunother
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
NEOPLASIAS
/
TERAPEUTICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos