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The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis

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Abstract

Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine TGF-β, 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-β signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-β-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-β signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.

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Abbreviations

TGF-β:

Transforming growth factor beta

TβRI:

Transforming growth factor beta-receptor type I

TβRII:

Transforming growth factor beta-receptor type II

TME:

Tumor microenvironment

TIC:

Tumor-infiltrating cells

FBS:

Fetal bovine serum

ELISA:

Enzyme-linked immunosorbent assay

IFN-γ:

Interferon-gamma

IL-4:

Interleukin-4

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Acknowledgments

We would like to acknowledge the help of the Immune Monitoring Laboratory at the Earle A. Chiles Research Institute. In particular, we would like to thank Dan Haley for help with flow cytometric analysis and Gwen Kramer for technical assistance. This work was supported by funds from The Providence Portland Medical Foundation.

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The authors report no conflict of interest.

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Authors and Affiliations

  1. Providence Portland Medical Center, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, 2N85, 4805 NE Glisan St, Portland, OR, 97213, USA

    Kendra Garrison, Tobias Hahn, Andrew D. Weinberg & Emmanuel T. Akporiaye

  2. Oncology Cell Signaling, Biogen Idec, Cambridge, MA, USA

    Leona E. Ling

  3. Shanghai Medicilon, Inc., Shanghai, China

    Wen-Cherng Lee

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  1. Kendra Garrison
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  2. Tobias Hahn
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Correspondence to Emmanuel T. Akporiaye.

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Garrison, K., Hahn, T., Lee, WC. et al. The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer Immunol Immunother 61, 511–521 (2012). https://doi.org/10.1007/s00262-011-1119-y

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