Abstracts of the 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)
- Poster presentation
- Open Access
STAT3 signaling is required for anti-OX40/TGF-β receptor blockade-mediated regression of large established tumors
Journal for ImmunoTherapy of Cancer volume 1, Article number: P68 (2013)
OX40 (CD134, TNFRSF4), a member of the tumor necrosis factor receptor (TNFR) superfamily is expressed on activated CD4+ and CD8+ T cells. In pre-clinical tumor models, agonist OX40 antibody (αOX40) therapy is often successful at treating small tumors but is less effective once the tumors have become established. For a tumor immunotherapy to be successful it will most likely require not only an agonist to boost effector T cell function but also an antagonist to eliminate T cell suppression. In this study, we show that agonist OX40 antibody synergizes with an orally bioavailable inhibitor of TGF-β (SM16) to elicit complete regression of large established tumors, resulting in long-term survival in 40-85% of αOX40/SM16 treated mice in two murine tumor models. Evaluation of tumor infiltrating T cells showed that SM16/αOX40 dual therapy resulted in an increase in OX40 and Granzyme B-expressing CD8+ T cells undergoing proliferation and which produced greater levels of IFNγ. We also found that this dual treatment led to an increase in pSTAT3 staining in both CD4+ and CD8+ T cells isolated from tumors. Therefore, we tested whether deletion of STAT3 in OX40 expressing cells would impact this potent combination therapy, since others have shown that pSTAT3 up-regulation is detrimental to T cell function within the tumor microenvironment. Surprisingly, deletion of STAT3 decreased the therapeutic efficacy of this combination therapy, suggesting that immune enhancement of T cells within tumor-bearing mice is reliant on signals through STAT3 to gain their full therapeutic potential.
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Akporiaye, E.T., Tucker, C., Triplett, T. et al. STAT3 signaling is required for anti-OX40/TGF-β receptor blockade-mediated regression of large established tumors. j. immunotherapy cancer 1 (Suppl 1), P68 (2013). https://doi.org/10.1186/2051-1426-1-S1-P68
- Tumor Microenvironment
- Tumor Model
- Treated Mouse
- Tumor Necrosis Factor Receptor
- Complete Regression