The TIE2-expressing monocytes (TEMs), has been shown to play an important role in tumor angiogenesis. Moreover, the specific elimination of TEMs in mouse tumor models inhibits tumor angiogenesis. We then asked whether the Tie2 ligand ANG2, which is secreted by angiogenic tumor blood vessels, could regulate the proangiogenic activity of TEMs. To this aim, we either neutralized ANG2 pharmacologically or knocked-down the TIE2 receptor specifically in TEMs by using a novel, conditional gene knock-down vector platform. We found that both ANG2 blockade and Tie2 gene knock-down specifically in TEMs delayed tumor angiogenesis and progression. Furthermore, ANG2 blockade strongly inhibited the growth of pulmonary metastases1 . These findings support the notion that targeting the ANG2/TIE2 angiogenic axis in tumors may represent a dual-target strategy that impairs both vascular cells and proangiogenic macrophages (TEMs).
Because TEMs are efficiently recruited to tumors, we previously exploited their tumor homing activity and selective expression of TIE2 to turn them into IFN-α delivery vehicles by engineering hematopoietic stem cells (HSCs) to express an IFN-α transgene under the control of the Tie2 promoter2 . Because TIE2 is also expressed by HSC, we developed vectors regulated by miR-126/130, which de-target transgene expression from HSC. Detargeting from HSC did not affect the ability of TEM-mediated IFN-α delivery to inhibit both primary and secondary spontaneous mammary tumors. We then constructed miR-regulated vectors carrying the human TIE2 promoter and tested them in human hematochimeric NSG mice. When mice were orthotopically injected with human breast cancer cells, IFN activity was induced at the tumor site. Importantly, by providing human IL-7, IL-15 and GM-CSF we improved reconstitution of human T, NK and myeloid cells in the NSG mice, and achieved effective antitumor response upon transplantation of TIE2-IFN transduced HSC. These results illustrate the therapeutic potential of a gene- and cell-based human platform for the specific delivery of IFN-α to treat established tumors.