ArticleCancer immunology, immunotherapy : CII2012
The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.
Article in Cancer immunology, immunotherapy : CII, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 66 citations in OpenAlex.
- OX40 signaling in cancer immunotherapy: mechanisms of action, translational applications, and therapeutic perspectives.Frontiers in immunology · 2026Review
- One step further in targeting acute leukemia by combining antibody-based immunotherapies and small molecule inhibitors.Cancer cell international · 2025Review
- Article
- Harnessing synergistic effects of MMP-2 Inhibition and bFGF to simultaneously preserve and vascularize cardiac extracellular matrix after myocardial infarction.Acta biomaterialia · 2025Article
- OX40/OX40L: a new target for tumor immunotherapy and its clinical research progress.Frontiers in oncology · 2025Review
- Multifunctional Nanovaccine Sensitizes Breast Cancer to Immune Checkpoint Therapy.Advanced functional materials · 2024Article
- Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives.Signal transduction and targeted therapy · 2024Review
- Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists.Molecular therapy. Nucleic acids · 2023Article
- Review
- Targeting integrin αvβ3 with indomethacin inhibits patient-derived xenograft tumour growth and recurrence in oesophageal squamous cell carcinoma.Clinical and translational medicine · 2021Article
- Emerging immunotherapies for metastasis.British journal of cancer · 2021Review
- Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations.Radiation oncology (London, England) · 2020Review
- Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response.Cancer immunology, immunotherapy : CII · 2020Article
- T-cell agonists in cancer immunotherapy.Journal for immunotherapy of cancer · 2020Review
- TGFβ suppresses CD8Nature communications · 2020Article
- Effects of Radiation on the Tumor Microenvironment.Seminars in radiation oncology · 2020Review
- Immune Checkpoint Blockade in Gastrointestinal Cancers: The Current Status and Emerging Paradigms.Journal of immunotherapy and precision oncology · 2020Review
- TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.Cancer immunology, immunotherapy : CII · 2019Article
- Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4Journal of translational medicine · 2019Article
- TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis.International journal of molecular sciences · 2019Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.