A TLR4–TRIF-dependent signaling pathway is required for protective natural tumor-reactive IgM production by B1 cells

Abstract

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous studies demonstrated a toll-like receptor 4 (TLR4) and C-type lectin receptor (CLR; Mincle/MCL) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits peritoneal tumor growth and ascites development through a mechanism dependent upon B-1a cellproduced natural IgM, complement, and phagocytes. In the current study, we investigated the requirement for TLR4 and Fc receptor common γ chain (FcRγ), required for Mincle/MCL signaling, in the MPL/TDCM-elicited response. MPL/TDCM significantly increased macrophages and Ly6C hi monocytes in the peritoneal cavity of both TLR4 −/− and FcRγ −/− mice, suggesting redundancy in the signals required for monocyte/macrophage recruitment. However, B1 cell activation, antibody secreting cell (ASC) differentiation, and tumor-reactive IgM production was defective in TLR4 −/− , but not FcRγ −/− mice. TRIF was required for production of IgM reactive against tumor-and mucin-related antigens, but not phosphorylcholine, whereas TLR4 was required for production of both types of reactivities. Consistent with this, B1 cells lacking TLR4 or TRIF did not proliferate or differentiate into tumor-reactive IgM-producing cells in vitro and did not reconstitute MPL/TDCM-dependent protection against peritoneal carcinomatosis in CD19 −/− mice. Our results indicate a TLR4/TRIF-dependent pathway is required by B1 cells for MPL/TDCM-elicited production of protective tumor-reactive natural IgM. The dependency on TRIF signaling for tumor-reactive, but not phosphorylcholine-reactive, IgM production reveals unexpected heterogeneity in TLR4-dependent regulation of natural IgM production, thereby highlighting important differences to consider when designing vaccines/therapies targeting these specificities.

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

“… 15 , 16 These series of reactions invoke immune cell infiltration 6 and activation. 17 In addition, Mincle −/− bone marrow-derived cells lose their ability in dynamic balance of pro- and anti-inflammatory cytokines, which affects cytotoxicity CD4 + T cell function such as interferon (IFN)-γ production. 18 Glycolipid-stimulated M1 polarization is another important immunomodulation in phagocytosis.…”

Role of TLR4 in Persistent Leptospira interrogans Infection: A Comparative In Vivo Study in Mice

“…For example, TLR4 expressed by B cells was shown to be key in early IgM production in mice, which is partially able to counteract Leptospira infection ( 4 ). We may speculate that early IgM production, activated three days post infection, may be linked to a role of TLR4, as it was recently shown that B1 cell activation and tumor-reactive IgM production were defective in TLR4 KO mice ( 25 ).…”

Role of TLR4 in persistentLeptospira interrogansinfection: a comparativein vivostudy in mice

“…For example, TLR4 expressed by B cells was shown to be key in early IgM production in mice, which is partially able to counteract Leptospira infection [4]. We may speculate that early IgM production, activated three days post infection, may be linked to a role of TLR4, as it was recently shown that B1 cell activation and tumor-reactive IgM production were defective in TLR4 KO mice [21].…”