Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms

Article (PDF Available)inJournal of Experimental Medicine 206(6):1317-26 · June 2009with83 Reads
DOI: 10.1084/jem.20082614 · Source: PubMed
Abstract
Carcinogenesis reflects the dynamic interplay of transformed cells and normal host elements, but cancer treatments typically target each compartment separately. Within the tumor microenvironment, the secreted protein milk fat globule epidermal growth factor-8 (MFG-E8) stimulates disease progression through coordinated alpha(v)beta(3) integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. We show that systemic MFG-E8 blockade cooperates with cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy to induce destruction of various types of established mouse tumors. The combination treatments evoke extensive tumor cell apoptosis that is coupled to efficient dendritic cell cross-presentation of dying tumor cells. This linkage engenders potent antitumor effector T cells but inhibits FoxP3(+) T reg cells, thereby achieving long-term protective immunity. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms.

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    • "C57BL/6 (H-2 b ) and BALB/c (H-2 d ) mice (8–12 weeks old) were purchased from Charles River Laboratories and maintained at the University of Ottawa according to the Canadian Council on Animal Care guidelines under the protocol approved by the Animal Use Subcommittee (permit BMI-2025). Recombinant mouse MFG-E8 (rmMFG-E8) was purchased from R&D Systems, and MFG-E8 antibody was prepared as described previously (Jinushi et al., 2009). Other antibodies used were described below or in Supplemental Experimental Procedures. "
    [Show abstract] [Hide abstract] ABSTRACT: The molecules and mechanisms pertinent to the low immunogenicity of undifferentiated embryonic stem cells (ESCs) remain poorly understood. Here, we provide evidence that milk fat globule epidermal growth factor 8 (MFG-E8) is a vital mediator in this phenomenon and directly suppresses T cell immune responses. MFG-E8 is enriched in undifferentiated ESCs but diminished in differentiated ESCs. Upregulation of MFG-E8 in ESCs increases the successful engraftment of both undifferentiated and differentiated ESCs across major histocompatibility complex barriers. MFG-E8 suppresses T cell activation/proliferation and inhibits Th1, Th2, and Th17 subpopulations while increasing regulatory T cell subsets. Neutralizing MFG-E8 substantially abrogates these effects, whereas addition of recombinant MFG-E8 to differentiated ESCs restores immunosuppression. Furthermore, we provide the evidence that MFG-E8 suppresses T cell activation and regulates T cell polarization by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor. Our findings offer an approach to facilitate transplantation acceptance.
    Full-text · Article · Oct 2015
    • "Similar findings have been reported for MFG-E8, which also participates in the phagocytosis of apoptotic cells. Administration of MFG-E8 to macrophages suppresses proinflammatory responses [57, 58], and MFG-E8 blocking antibodies while ineffective as single agents result in tumor control when combined with chemotherapy or radiation therapy [59]. Since MFG-E8 signaling occurs in part through Mertk [32], it is possible that Mertk knockout mice lose the effects of both MFG-E8 and Gas6 mediated recognition of apoptotic cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFβ inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.
    Article · Nov 2014
    • "In the mouse, Mfge8 promotes phagocytosis of apoptotic cells by macrophages [6], and skews them to secrete tolerogenic cytokines [7]. On some tumor cells themselves, MFGE8 was shown to induce epithelial to mesenchymal transition [8,9], and/or to increase resistance to drug-induced apoptosis [10,11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Milk Fat Globule - EGF - factor VIII (MFGE8), also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvβ3 and αvβ5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients.
    Full-text · Article · Aug 2013
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