Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor-Targeted Therapy

被引:64
作者
Bedi, Atul [1 ,2 ,3 ]
Chang, Xiaofei [1 ]
Noonan, Kimberly [2 ]
Vui Pham [1 ]
Bedi, Rishi [1 ]
Fertig, Elana J. [2 ]
Considine, Michael [2 ]
Califano, Joseph A. [1 ,3 ]
Borrello, Ivan [2 ,3 ]
Chung, Christine H. [2 ,3 ]
Sidransky, David [1 ,2 ,3 ]
Ravi, Rajani [1 ,2 ]
机构
[1] Johns Hopkins Univ, Head & Neck Canc Res Div, Dept Otolaryngol Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA
[2] Johns Hopkins Univ, Dept Oncol, Sch Med, Baltimore, MD 21231 USA
[3] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sch Med, Baltimore, MD 21231 USA
关键词
GROWTH-FACTOR RECEPTOR; SQUAMOUS-CELL CARCINOMA; CANCER-THERAPY; FC-RECEPTORS; MONOCLONAL-ANTIBODIES; EXTRACELLULAR DOMAIN; ACQUIRED-RESISTANCE; TUMOR ANGIOGENESIS; COLORECTAL-CANCER; CETUXIMAB;
D O I
10.1158/1535-7163.MCT-12-0101-T
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 gamma 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-beta. We show that TGF-beta suppresses the expression of key molecular effectors of immune cell-mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-gamma. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-beta-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-beta compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-beta-overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-beta-blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-beta in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-beta 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-beta to improve anti-EGFR-specific antibody therapy of EGFR-expressing cancers. Mol Cancer Ther; 11(11); 2429-39. (C) 2012 AACR.
引用
收藏
页码:2429 / 2439
页数:11
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