Transforming growth factor beta (TGF \#946;) is a multifunctional cytokine that profoundly regulates the pathogenesis of cancer and metastasis. TGF \#946; signaling not only regulates cellular biological functions in promoting tumor growth, metastasis, angiogenesis, and inflammation but also mediates immunosuppression during tumor progression. Regulatory T (Treg) cells have been reported to be an important mediator in suppressing antitumor immunity. Inhibition of Treg cells and enhancement of immune response have been a challenge undertaking for facilitating weakened immunity to improve therapeutic efficacy against cancer. Here, we report that we have developed monoclonal antibodies with specific blocking activity to TGF \#946; stimulation of TGF \#946; receptor II (TGF \#946; RII) mediated downstream signaling activation, and that by using the antibody we have investigated the mechanisms of action of TGF \#946; RII mediated activity in suppressing T cell activation and the role of TGF \#946; RII+ Treg cells in tumor growth and metastasis. We found that anti-TGF \#946; RII antibody inhibited in vitro TGF \#946; induced conversion of naive T cells into Treg cells and Treg cell mediated inhibition of T cell proliferation stimulated by anti-CD3 antibody engagement of T cell receptor (TCR) and antigen presenting cells (APC). More importantly, anti-TGF \#946; RII antibody treatment of tumor bearing mice resulted in significant inhibition of Treg cells and depletion of TGF \#946; RII+ Treg cells. The results in these studies indicated that anti-TGF \#946; RII antibody has the capacity of depleting TGF \#946; receptor II+ Treg cells and inhibiting TGF \#946; induction of Treg cells and Treg cell mediated suppression of T cell responses. In addition, anti-TGF \#946; RII antibody treatment increased natural killer (NK) and cytotoxic T lymphocyte (CTL) activity and elevated production of interferon gamma (IFN-\#947;) in NK and CD8 T cells in spleens from the antibody treated tumor bearing immunocompetent mice. Collectively, this study has demonstrated that anti-TGF \#946; RII antibody has the ability to enhance adaptive antitumor immunity through attenuating TGF \#946; mediated immunosuppression and facilitating NK and CTL activity in controlling tumor progression, and provides compelling data supporting the notion that a neutralizing anti-TGF \#946; RII antibody may represent a novel therapeutic strategy to accelerate antitumor immunity for combating cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5659.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO