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Volume 1 Supplement 1

Abstracts of the 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)

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STAT3 signaling is required for anti-OX40/TGF-β receptor blockade-mediated regression of large established tumors

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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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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).

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