IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer.


Jordakieva G(1), Bianchini R(2)(3), Reichhold D(4), Piehslinger J(4), Groschopf A(2)(3)(5), Jensen SA(6), Mearini E(7), Nocentini G(8), Crevenna R(1), Zlabinger GJ(9), Karagiannis SN(10)(11), Klaus A(4), Jensen-Jarolim E(2)(3).
Author information:
(1)Department of Physical Medicine, Rehabilitation and Occupational Medicine, Vienna, Austria.
(2)The Interuniversity Messerli Research Institute of the University of Veterinary Medicine, the Medical University of Vienna and the University of Vienna, Unit of Comparative Medicine, Vienna, Austria.
(3)Institute Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Division of Comparative Immunology and Oncology, Medical University of Vienna, Vienna, Austria.
(4)Department of General Surgery, Barmherzige Schwestern Krankenhaus Wien, Vienna, Austria.
(5)FH Campus Wien, Department of Health Science, Section of Biomedical Analytics, University of Applied Sciences, Vienna, Austria.
(6)Department of General Surgery, Medical University of Vienna, Vienna, Austria.
(7)Department of Surgical and Biomedical Sciences, Urology Clinic of Perugia, University of Perugia, Perugia, Italy.
(8)Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy.
(9)Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
(10)St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, UK.
(11)Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, UK.


IgG4 subclass antibodies are expressed in alternative Th2 environments featuring high IL-10 expression, including several solid tumors such as melanoma. To induce tolerance, allergen immunotherapy mediates antibody class switching from pro-inflammatory IgE to anti-inflammatory IgG4. We previously reported that IgG4 drives allergic M2 macrophages toward tolerogenic states. Here we assessed the roles of IgG4 and macrophage activation in colorectal cancer (CRC). In this observer-blinded, case-control study, we analyzed total circulating serum IgE, IgG1 and IgG4 levels in CRC (n = 38) patients with (n = 13, TxNxM1) or without (n = 25, TxNxM0) metastasis, and in healthy donors (n = 21). Primary cultures of circulating monocyte-derived macrophages from healthy controls and CRC patients were further evaluated in their responses to stimulation with IgG1 or IgG4. We found higher absolute serum levels of IgG4 in patients with CRC. IgG4 enabled polarization of macrophages derived from CRC patients and healthy controls into alternatively-activated tolerogenic M2b phenotypes. IgG4-stimulated M2 macrophages were characterized by lower surface CD206, CD163, CD14, and CD11b expression and higher CCL-1, IL-10, and IL-6 production. IgG4 was less potent that IgG1 in triggering antibody-dependent cell-mediated phagocytosis (ADCP) of cancer cells. Further, higher z-normalized IgG4/-IgE sera level ratios correlated with the presence of metastasis (p = .0247 and p = .0009, respectively) in CRC patients. High IgG4 in CRC synergizes with macrophages in shaping an immunosuppressive microenvironment and impairs anti-cancer effector cell functions. The shift of serum IgG4/IgE ratios toward enhanced tolerance induction in metastatic disease indicates a role for high IgG4 in disease progression and poor prognostic outcome.