Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism

Abstract

The A v B 6 integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of A v B 6 expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of A v B 6 in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent A v B 6 expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate A v B 6 expression. Detroit 562 cells showed A v B 6 -dependent adhesion and activation of transforming growth factor-B (TGF-B) that was inhibited >90% with an A v B 6 blocking antibody, 6.3G9. Although both recombinant soluble TGF-B receptor type-II (rsTGF-BRII-Fc) and 6.3G9 inhibited TGF-B-mediated Smad2/ 3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-BRII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by A v B 6 antibodies, our findings support a role for A v B 6 in human cancer and underscore the therapeutic potential of function blocking A v B 6 antibodies. [Cancer Res 2008;68(2):561-70]

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

“…This observation is in accordance with various studies that have reported the role of integrin β 6 in mediating metastasis 15, 34, 35. However, as indicated on the graph (Fig.…”

αvβ6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation

“…These data suggest that avh6 is an attractive tumor target, and several studies have now inhibited tumor growth successfully in vivo using treatments directed against the integrin (33,34). Surprisingly, inhibition of avh6 had no effect on NTGli1 cell Transwell invasion (Fig.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…A more fruitful approach may be to target proteins with a more restricted tissue expression profile than that of the TGF-b receptors, which might affect the TGF-b activity only in specific cells of the TME such as in DCs, NK cells, MDSCs and/or T cells. Integrins that activate TGF-b have been considered as such drug targets (Van Aarsen et al 2008;Dutta et al 2014). Another example is GARP, which is required for activation of latent TGF-b on Tregs and platelets (Stockis et al 2009;Tran et al 2009).…”

“…This antibody may therefore impose a more specific TGF-b blockade immunotherapy for cancer, probably with fewer side effects than blocking TGF-b receptors or ligands, because of the restricted pattern of GARP expression. Other TGF-b modulatory drugs are in development for various disease applications including oncology (Van Aarsen et al 2008;Henderson et al 2013;Salvo et al 2014).…”