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 Fertig, Michael Considine, Joseph A. Califano, Ivan M 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 2012

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Epidermal Growth Factor Receptor
Neoplasms
Therapeutics
Antibody-Dependent Cell Cytotoxicity
Granzymes
Blocking Antibodies
Fas Ligand Protein
Tumor Microenvironment
Fc Receptors
Genetic Selection
Heterografts
Monoclonal Antibodies
Cetuximab
Apoptosis
Ligands
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of TGF-β enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. / Bedi, Atul; Chang, Xiaofei; Noonan, Kimberly; Pham, Vui; Bedi, Rishi; Fertig, Elana; Considine, Michael; Califano, Joseph A.; Borrello, Ivan M; Chung, Christine H.; Sidransky, David; Ravi, Rajani.

In: Molecular Cancer Therapeutics, Vol. 11, No. 11, 11.2012, p. 2429-2439.

Research output: Contribution to journalArticle

Bedi, Atul ; Chang, Xiaofei ; Noonan, Kimberly ; Pham, Vui ; Bedi, Rishi ; Fertig, Elana ; Considine, Michael ; Califano, Joseph A. ; Borrello, Ivan M ; Chung, Christine H. ; Sidransky, David ; Ravi, Rajani. / Inhibition of TGF-β enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 11. pp. 2429-2439.
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