Abstract
IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127-41. ©2017 AACR.
Highlights
Engagement of tumor-specific mAbs via their Fc receptors contributes significantly to the antitumor effects of the immune system [1]
We report the superior antitumor efficacy of tumor-associated antigen (TAA)-specific IgE in an immunocompetent syngeneic rat model of cancer, uniquely suitable for the study of IgE antitumor effector functions
The functional significance of this IgE-induced TNFa/MCP-1 axis is supported by: (i) enhanced intratumor infiltration by macrophages following IgE treatments; (ii) a TNFa-expressing lung macrophage compartment and elevated TNFa and MCP-1 concentrations in bronchoalveolar lavage (BAL) from IgE- but not IgG-treated rats; (iii) macrophage recruitment correlating with tumor growth restriction in IgE-treated syngeneic rat and human xenograft mouse models of cancer; (iv) the ability of human IgE to trigger monocytes to upregulate TNFa in a class-specific manner; (v) the induction of MCP-1 production by TNFa in monocytes and tumor cells, in turn shown to promote a monocyte chemotactic
Summary
Engagement of tumor-specific mAbs via their Fc receptors contributes significantly to the antitumor effects of the immune system [1]. Focusing effector cells, such as monocytes/macrophages and natural killer (NK) cells, against cancer-associated components may contribute to the functions of therapeutic antibodies, such as trastuzumab, cetuximab, and the checkpoint inhibitor ipilimumab [2, 3]. The potential of IgE to induce inflammatory responses at tumor sites may be harnessed through IgE receptor–expressing effector cells, such as monocytes and macrophages in tumors Strategies to implement this approach include recombinant tumor-associated antigen (TAA)-specific IgEs and active immunotherapy triggering adaptive IgE responses against cancer [8,9,10,11,12]
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