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

Debra H. Josephs; Heather J. Bax; Tihomir Dodev; Mirella Georgouli; Mano Nakamura; Giulia Pellizzari; Louise Saul; Panagiotis Karagiannis; Anthony Cheung; Cecilia Herraiz; Kristina M. Ilieva; Isabel Correa; Matthew Fittall; Silvia Crescioli; Patrycja Gazinska; Natalie Woodman; Silvia Mele; Giulia Chiaruttini; Amy E. Gilbert; Alexander Koers; Marguerite Bracher; Christopher Selkirk; Heike Lentfer; Claire Barton; Elliott Lever; Gareth Muirhead; Sophia Tsoka; Silvana Canevari; Mariangela Figini; Ana Montes; Noel Downes; David Dombrowicz; Christopher J. Corrigan; Andrew J. Beavil; Frank O. Nestle; Paul S. Jones; Hannah J. Gould; Victoria Sanz-Moreno; Philip J. Blower; James F. Spicer; Sophia N. Karagiannis

doi:10.1158/0008-5472.CAN-16-1829

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

Debra H. Josephs, Heather J. Bax, Tihomir Dodev, Mirella Georgouli, Mano Nakamura, Giulia Pellizzari, Louise Saul, Panagiotis Karagiannis, Anthony Cheung, Cecilia Herraiz, Kristina M. Ilieva, Isabel Correa, Matthew Fittall, Silvia Crescioli, Patrycja Gazinska, Natalie Woodman, Silvia Mele, Giulia Chiaruttini, Amy E. Gilbert, Alexander KoersMarguerite Bracher, Christopher Selkirk, Heike Lentfer, Claire Barton, Elliott Lever, Gareth Muirhead, Sophia Tsoka, Silvana Canevari, Mariangela Figini, Ana Montes, Noel Downes, David Dombrowicz, Christopher J. Corrigan, Andrew J. Beavil, Frank O. Nestle, Paul S. Jones, Hannah J. Gould, Victoria Sanz-Moreno, Philip J. Blower, James F. Spicer, Sophia N. Karagiannis^*

^*Corresponding author for this work

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Abstract

IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent 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-Fce 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.

Original language	English
Pages (from-to)	1127-1141
Number of pages	15
Journal	Cancer Research
Volume	77
Issue number	5
Early online date	17 Jan 2017
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-1829
Publication status	Published - 31 Mar 2017

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10.1158/0008-5472.CAN-16-1829

Anti-folate receptor-α IgE_JOSEPHS_Accepted19Dec2016_GREEN AAMAccepted author manuscript, 11.6 MB

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Josephs, D. H., Bax, H. J., Dodev, T., Georgouli, M., Nakamura, M., Pellizzari, G., Saul, L., Karagiannis, P., Cheung, A., Herraiz, C., Ilieva, K. M., Correa, I., Fittall, M., Crescioli, S., Gazinska, P., Woodman, N., Mele, S., Chiaruttini, G., Gilbert, A. E., ... Karagiannis, S. N. (2017). Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/MCP-1 signaling. Cancer Research, 77(5), 1127-1141. https://doi.org/10.1158/0008-5472.CAN-16-1829

@article{29dc564d246b42da9b7a7f3d01f3309f,

title = "Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/MCP-1 signaling",

abstract = "IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent 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-Fce 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.",

author = "Josephs, {Debra H.} and Bax, {Heather J.} and Tihomir Dodev and Mirella Georgouli and Mano Nakamura and Giulia Pellizzari and Louise Saul and Panagiotis Karagiannis and Anthony Cheung and Cecilia Herraiz and Ilieva, {Kristina M.} and Isabel Correa and Matthew Fittall and Silvia Crescioli and Patrycja Gazinska and Natalie Woodman and Silvia Mele and Giulia Chiaruttini and Gilbert, {Amy E.} and Alexander Koers and Marguerite Bracher and Christopher Selkirk and Heike Lentfer and Claire Barton and Elliott Lever and Gareth Muirhead and Sophia Tsoka and Silvana Canevari and Mariangela Figini and Ana Montes and Noel Downes and David Dombrowicz and Corrigan, {Christopher J.} and Beavil, {Andrew J.} and Nestle, {Frank O.} and Jones, {Paul S.} and Gould, {Hannah J.} and Victoria Sanz-Moreno and Blower, {Philip J.} and Spicer, {James F.} and Karagiannis, {Sophia N.}",

note = "Copyright {\textcopyright}2017, American Association for Cancer Research.",

year = "2017",

month = mar,

day = "31",

doi = "10.1158/0008-5472.CAN-16-1829",

language = "English",

volume = "77",

pages = "1127--1141",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "5",

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Josephs, DH, Bax, HJ , Dodev, T , Georgouli, M, Nakamura, M, Pellizzari, G , Saul, L, Karagiannis, P, Cheung, A, Herraiz, C, Ilieva, KM, Correa, I, Fittall, M, Crescioli, S, Gazinska, P, Woodman, N, Mele, S, Chiaruttini, G, Gilbert, AE, Koers, A , Bracher, M, Selkirk, C, Lentfer, H, Barton, C, Lever, E, Muirhead, G , Tsoka, S, Canevari, S, Figini, M, Montes, A, Downes, N, Dombrowicz, D, Corrigan, CJ , Beavil, AJ, Nestle, FO, Jones, PS, Gould, HJ , Sanz-Moreno, V , Blower, PJ , Spicer, JF & Karagiannis, SN 2017, 'Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/MCP-1 signaling', Cancer Research, vol. 77, no. 5, pp. 1127-1141. https://doi.org/10.1158/0008-5472.CAN-16-1829

TY - JOUR

T1 - Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/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 J.

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 F.

AU - Karagiannis, Sophia N.

PY - 2017/3/31

Y1 - 2017/3/31

N2 - IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent 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-Fce 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.

AB - IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent 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-Fce 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.

UR - http://www.scopus.com/inward/record.url?scp=85015827591&partnerID=8YFLogxK

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

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

M3 - Article

C2 - 28096174

SN - 0008-5472

VL - 77

SP - 1127

EP - 1141

JO - Cancer Research

JF - Cancer Research

IS - 5

ER -

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

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