Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells

Zhaojing Zhong, Kyla Driscoll Carroll, Desiree Policarpio, Carla Osborn, Michael Gregory, Rajiv Bassi, Xenia Jimenez, Marie Prewett, Gregory Liebisch, Kris Persaud, Douglas Burtrum, Su Wang, David Surguladze, Stanley Ng, Heather Griffith, Paul Balderes, Jacqueline Doody, Jonathan D. Schwartz, Hagop Youssoufian, Eric K. RowinskyDale L. Ludwig, Larry Witte, Zhenping Zhu, Yan Wu

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti-TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models. Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models. Results: Anti-TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumorbearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis. Conclusions: These preclinical data provide a foundation to support using anti-TGFβ RII antibody as a therapeutic agent for TGFβ RIIβdependent cancer with metastatic capacity.

Original languageEnglish
Pages (from-to)1191-1205
Number of pages15
JournalClinical Cancer Research
Volume16
Issue number4
DOIs
StatePublished - 15 Feb 2010
Externally publishedYes

Fingerprint

Dive into the research topics of 'Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells'. Together they form a unique fingerprint.

Cite this