Cancer Immunology, Immunotherapy

, Volume 61, Issue 4, pp 511–521

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

  • Kendra Garrison
  • Tobias Hahn
  • Wen-Cherng Lee
  • Leona E. Ling
  • Andrew D. Weinberg
  • Emmanuel T. Akporiaye
Original article

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.

Keywords

Breast cancer 4T1 OX40 TGF-β TGFβRI/ALK5 Small molecule kinase inhibitor SM16 

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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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kendra Garrison
    • 1
  • Tobias Hahn
    • 1
  • Wen-Cherng Lee
    • 3
  • Leona E. Ling
    • 2
  • Andrew D. Weinberg
    • 1
  • Emmanuel T. Akporiaye
    • 1
  1. 1.Providence Portland Medical Center, Robert W. Franz Cancer Research Center, Earle A. Chiles Research InstitutePortlandUSA
  2. 2.Oncology Cell Signaling, Biogen IdecCambridgeUSA
  3. 3.Shanghai Medicilon, Inc.ShanghaiChina

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