TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2–Expressing Monocytes in Human Breast Tumors

Abstract

Purpose: Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs.Experimental Design: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas.Results: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells.Conclusions: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response.

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

“…Tie2 + macrophages have been shown to release IL-10 and thereby suppress CD8 + cytotoxic T cells, expand immunosuppressive Tregs, and cause dendritic cell anergy (22,29). It has also been reported that in long-term responding subjects treated with anti-CTLA4 agents, a humoral reaction is generated against angiopoietins (68).…”

“…In particular, tumor-associated macrophages (TAMs) not only promote cancer growth, cancer cell survival and motility (7,19–23), but can limit the efficacy of the tumor response to chemotherapy or radiotherapy (24–28). Tie2 + macrophages are known to be pro-angiogenic, pro-metastatic, and immunosuppressive in the tumor microenvironment (2,15,22,29). In pre-clinical studies of mammary carcinoma, Ang2 blockade impeded the association of Tie2 + macrophages with the nascent tumor vasculature, thereby suppressing their pro-angiogenic activity (8) and their pro-metastatic potential (8,30).…”

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

“…For example, an accumulation of TEMs at the tumor site has recently been reported to mediate resistance to antiangiogenic (anti-VEGF) cancer treatment 17 and may be altered by the therapy. 18 Based on our previous study demonstrating a selective rise and a marker potential of intermediate monocytes in CRC patients, 16 we further hypothesized that CRC therapy has an impact on the frequency and function of intermediate monocytes (and possibly the TEM subset). Thus, we aimed to: (1) define the phenotypical and functional properties of intermediate monocytes from mCRC patients and (2) investigate if these properties are affected by neoadjuvant chemotherapy with or without the addition of the VEGF inhibitor bevacizumab (Avastin Ò ).…”

Engineered tumor-infiltrating macrophages as gene delivery vehicles for interferon-α activates immunity and inhibits breast cancer progression

“…Recent studies have shown that tumor-infiltrating TEMs exert immunosuppressive and pro-angiogenic activity in human breast cancer and have implicated IFNα signaling to host immune cells as a key suppressor mechanism of bone metastases originating from primary breast tumors 7 , 8 . These results, together with our own, could revive interest in testing autologous HSPC transplantation in advanced breast cancer patients with the aim to effectively reprogram the tumor microenvironment and counteract the protumor activity of this endogenous population.…”