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.