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

Abstract

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.

Serum IgG4 levels at diagnosis can predict unfavorable outcomes of untreated patients with IgG4-related disease

“…Twenty-seven of these patients were followed up without treatment after the initial diagnosis. The following clinical factors at the time of diagnosis were retrospectively determined: age; gender; history of allergy; serum levels of IgG, IgG4, IgE, C3, C4, CH50, C-reactive protein (CRP), and creatinine; serum IgG4/IgE ratio 24 ; peripheral blood eosinophil counts; presence of rheumatoid factor (RF) and anti-nuclear antibodies (ANA); number of affected organs; involvement of pancreas, salivary glands, ophthalmus, kidney, aorta/artery, retroperitoneum, and lung; IgG4-RD responder index. We compared the clinical features of these 27 patients with those of the 80 patients who underwent treatment.…”

Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity

“…Yet, we would be remiss if we failed to mention some caveats (1): AOM/DSS is only one model of CRC and other timepoints of delivery in the regime were not considered although one would hypothesis that early delivery of M(IL4)s could be beneficial because of their anti-colitic ability (2); it is possible that in other models or in humans that in vivo factors [e.g. IgG 4 (50)] could promote an oncogenic phenotype in the M(IL4)s; and (3), while functionally equivalent in some aspects, human and murine M(IL4)s are not identical and findings with murine cells do not dismiss the possibility that human M(IL4)s could promote CRC, metastasis or cancer in other organs.…”

Cancer: Still a contraindication for allergen immunotherapy?

“…Elevated IgG4 levels in colorectal cancer actively collaborate with macrophages to model an immunosuppressive microenvironment; this may also impair the functions of the anticancer effector cells. 16 The shift of serum IgG4/IgE indicates a role for high IgG4 in disease progression and could have a poor prognostic outcome in metastatic disease, as it could enhance tolerance induction. 16 IgG4 could have a protective role similar to a blocking antibody as well as the stimulation of the secretion of CCL1 and IL-10 to support a regulatory cell recruitment and help to modulate a tolerogenic environment.…”

“… 16 The shift of serum IgG4/IgE indicates a role for high IgG4 in disease progression and could have a poor prognostic outcome in metastatic disease, as it could enhance tolerance induction. 16 IgG4 could have a protective role similar to a blocking antibody as well as the stimulation of the secretion of CCL1 and IL-10 to support a regulatory cell recruitment and help to modulate a tolerogenic environment. 17 , 18 , 19 This could be achieved due to the chronic antigenic stimulus that directs the change of the B cells to IgG4 as well as the subsequent change of state of the macrophage subtype M2a towards the M2b that would secrete CCL1 and IL-10.…”

“…These increases must be related to elevated IL-10 production and suppression of the late response. 16 Patients' sera after allergen immunotherapy have IgG-associated IgE-blocking activity for both basophil activation (increased allergen stimulated basophil CD63) and IgE-FAB inhibition that paralleled increases in IgG4 levels. 21 High-dose allergen exposure, including allergen specific immunotherapy, restores dendritic cell activity, which produces IL-12, IL-27, and IL-10 and promotes immune deviation from a Th2 to Th1 response and induction of Treg and Breg cells that produce IgA, IgG, and IgG4 blocking antibodies.…”