Inhibition of TGF-? 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 Fc? 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-?. We show that TGF-? suppresses the expression of key molecular effectors of immune cell-mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-?. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-?-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-? compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-?-overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-?-blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-? in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-? 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-? to improve anti-EGFR-specific antibody therapy of EGFR-expressing cancers.

SUBMITTER: Bedi A 

PROVIDER: S-EPMC3640459 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature