Inhibition of TGF-β enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy

Atul Bedi, Xiaofei Chang, Kimberly Noonan, Vui Pham, Rishi Bedi, Elana J. Fertig, Michael Considine, Joseph A. Califano, Ivan Borrello, Christine H. Chung, David Sidransky, Rajani Ravi

Research output: Contribution to journalArticle

Abstract

EGF receptor (EGFR)-targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor-ligand interactions and engagement of Fcγ receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-β. We show that TGF-β suppresses the expression of key molecular effectors of immune cell-mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-γ. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-β-mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell-mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-β compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGFβ-overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-β-blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-β in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-β is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-β to improve anti-EGFR-specific antibody therapy of EGFR-expressing cancers.

Original languageEnglish (US)
Pages (from-to)2429-2439
Number of pages11
JournalMolecular cancer therapeutics
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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