Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNF-α/MCP-1 signaling

TY - JOUR

T1 - Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNF-α/MCP-1 signaling

AU - Josephs, Debra H

AU - Bax, Heather J

AU - Dodev, Tihomir

AU - Georgouli, Mirella

AU - Nakamura, Mano

AU - Pellizzari, Giulia

AU - Saul, Louise

AU - Karagiannis, Panagiotis

AU - Cheung, Anthony

AU - Herraiz, Cecilia

AU - Ilieva, Kristina M

AU - Correa, Isabel

AU - Fittall, Matthew

AU - Crescioli, Silvia

AU - Gazinska, Patrycja

AU - Woodman, Natalie

AU - Mele, Silvia

AU - Chiaruttini, Giulia

AU - Gilbert, Amy E

AU - Koers, Alexander

AU - Bracher, Marguerite

AU - Selkirk, Christopher

AU - Lentfer, Heike

AU - Barton, Claire

AU - Lever, Elliott

AU - Muirhead, Gareth

AU - Tsoka, Sophia

AU - Canevari, Silvana

AU - Figini, Mariangela

AU - Montes, Ana

AU - Downes, Noel

AU - Dombrowicz, David

AU - Corrigan, Christopher

AU - Beavil, Andrew J

AU - Nestle, Frank O

AU - Jones, Paul S

AU - Gould, Hannah J

AU - Sanz-Moreno, Victoria

AU - Blower, Philip J

AU - Spicer, James

AU - Karagiannis, Sophia N

N1 - Copyright ©2017, American Association for Cancer Research.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - IgE antibodies are key mediators of anti-parasitic immune responses, but their potential for cancer treatment via antibody-directed 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 monoclonal antibodies 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 intra-tumoral 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 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 anti-tumor 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.

AB - IgE antibodies are key mediators of anti-parasitic immune responses, but their potential for cancer treatment via antibody-directed 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 monoclonal antibodies 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 intra-tumoral 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 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 anti-tumor 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.

U2 - 10.1158/0008-5472.CAN-16-1829

DO - 10.1158/0008-5472.CAN-16-1829

M3 - SCORING: Journal article

C2 - 28096174

VL - 77

SP - 1127

EP - 1141

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 5

ER -