The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy

Abstract

The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non–small cell lung cancer (NSCLC) tumor models. Factors shed by ADAM17 from NSCLC tumor cells (A549, H358) and relevant for endothelial cell migration were investigated using transwell migration assays, ELISA, and flow cytometry. Tumor angiogenesis–related endpoints were analyzed with the chorio-allantoic membrane assay and in murine NSCLC tumor models. Efficacy-oriented experiments were performed in a murine orthotopic NSCLC tumor model using irradiation with an image-guided small-animal radiotherapy platform alone and in combination with the novel ADAM17-directed antibody MEDI3622. In vitro, VEGF was identified as the major factor responsible for IR-induced and ADAM17-dependent endothelial cell migration toward attracting tumor cells. IR strongly enhanced tumor cell–associated ADAM17 activity, released VEGF in an ADAM17-dependent manner, and thereby coordinated the communication between tumor and endothelial cells. In vivo, tumor growth and microvessel size and density were strongly decreased in response to the combined treatment modality of IR and MEDI3622 but not by either treatment modality alone and thus suggest that the supra-additive effect of the combined treatment modality is in part due to abrogation of the ADAM17-mediated IR-induced protective effect on the tumor vasculature. Furthermore, we demonstrate that the novel ADAM17-inhibitory antibody MEDI3622 potently improves the radiotherapy response of NSCLC. Significance: The tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…In addition, iRhom2, as a key binding protein for ADAM17, further promotes KRAS-induced tumor cell growth by modulating the release of ERBB ligands (196). However, the efficacy of radiotherapy for non-small cell lung cancer was enhanced when blockade of ADAM17 function with the neutralizing antibody (197). These findings suggest that ADAM17 is a cancer-promoting gene and a potential target for anti-lung cancer therapies.…”

The role of EphA2 in ADAM17- and ionizing radiation-enhanced lung cancer cell migration

“…Doxycycline-treated cells were seeded into the inserts and starved in 0.5% FBS containing cell growth media. Cell migration towards growth media supplemented with 1.0% FBS was quantified 48 hours following sham-irradiation or irradiation of the inserts with the sublethal dose of 5 Gy ( 21 ). Basal cell migration of NCI-H358 control cells was enhanced in response to irradiation, while basal and IR-enhanced migration was strongly abrogated in EphA2 knockdown cells ( Figure 1A ).…”

“…We recently reported that IR-induced endothelial cell migration is strongly mediated by tumor cell-located ADAM17 ( 19 , 21 ). In subcutaneous and orthotopic lung tumor models, ADAM17 inhibition by the novel ADAM17-specific therapeutic antibody MEDI3622 in combination with radiotherapy induced a strong anti-angiogenic effect and tumor shrinkage ( 21 ).…”

“…We recently reported that IR-induced endothelial cell migration is strongly mediated by tumor cell-located ADAM17 ( 19 , 21 ). In subcutaneous and orthotopic lung tumor models, ADAM17 inhibition by the novel ADAM17-specific therapeutic antibody MEDI3622 in combination with radiotherapy induced a strong anti-angiogenic effect and tumor shrinkage ( 21 ). MEDI3622 was also previously investigated alone and in combination with anti-EGFR–targeting agents in preclinical colorectal and esophageal tumor models demonstrating promising antitumor activity ( 25 , 26 ).…”

“…ADAM17 is involved in the processing of the extracellular matrix and the release of various growth factors and cytokines that contribute to the remodeling of the TME and facilitate tumor cell dissemination ( 19 ). We recently have shown that IR enhances ADAM17 activity in NSCLC cell lines which contributes not only to the radioprotection of the tumor itself, but also its vasculature ( 20 , 21 ). Here, we investigate IR-induced tumor cell motility and link it mechanistically to an IR-enhanced ADAM17-EphA2 signaling network acting on an auto- and paracrine level.…”