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

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 αvβ3 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.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…Mfge8 can regulate the differentiation of naive T cells into regulatory T cells (Tregs) and Th1 and Th17 cells (14)(15)(16). Each of these cell types has defined roles in asthma (17)(18)(19)(20).…”

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…For instance, systemic MFG-E8 blockade increases the effectiveness of conventional chemoradiotherapy and anticancer vaccines by augmenting apoptosis and potentiating DC-driven immunity. 117 Conclusions. The process of phagocytosis was discovered more than a century ago, much before the finer details of cell death regulation and mechanisms came to be described.…”

MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells

“…It has been shown that functionally blocking anti-MFG-E8 antibodies induced the regression of experimental breast cancers (Ceriani et al, 1987) and acted synergistically with conventional chemotherapy to reduce experimental colon carcinomas, melanomas and lymphomas (Jinushi et al, 2009); in addition, triple-negative breast cancer cells in which MFG-E8 expression was silenced were more sensitive to cisplatin treatment (Yang et al, 2011). Taken together with this published evidence, our present results support the idea that combinatorial therapies that include MFG-E8 blockade may be operative in the treatment of some breast cancer patients.…”

“…Moreover, when these cells were injected in mice, MFG-E8 enhanced tumor growth through the inhibition of antitumor immune responses (Jinushi et al, 2008). In line with this, functionally blocking antibodies against MFG-E8 potentiated the effects of chemotherapeutic agents on experimental melanomas, colon carcinomas and lymphomas (Jinushi et al, 2009). In the mammary gland, MFG-E8 expression increases during pregnancy, lactation and subsequent mammary gland involution (Oshima et al, 1999;Hanayama and Nagata, 2005).…”