Anti-Folate Receptor-? IgE but not IgG Recruits Macrophages to Attack Tumors via TNF?/MCP-1 Signaling.

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-Fc? receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FR?), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FR?. Compared with IgG, anti-FR? IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNF?+ and CD80+ macrophages plus elevated TNF? and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNF? 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 TNF?, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNF? 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.

SUBMITTER: Josephs DH 

PROVIDER: S-EPMC6173310 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature