title: Inhibition of TGF-β enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy.
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 TGF-β-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.
authors.affiliation: Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, 1550 Orleans Street, Johns Hopkins University School of Medicine, Cancer Research Building II, Baltimore, MD 21231, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Bedi
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chang
authors.forename: Kimberly
authors.initials: K
authors.lastname: Noonan
authors.forename: Vui
authors.initials: V
authors.lastname: Pham
authors.forename: Rishi
authors.initials: R
authors.lastname: Bedi
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.forename: Michael
authors.initials: M
authors.lastname: Considine
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Rajani
authors.initials: R
authors.lastname: Ravi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000097:blood; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000068818:Cetuximab