Tumor-B-cell interactions promote isotype switching to an immunosuppressive IgG4 antibody response through upregulation of IL-10 in triple negative breast cancers

Abstract

Background Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC. Methods We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. Results Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. Conclusions These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.

Pro-tumor Tfh2 cells induce detrimental IgG4 production and PGE2-dependent IgE inhibition in pancreatic cancer

“… 64 , 70 , 71 , 72 Previous studies have shown that high levels of IgG4 in the tumor correlated with reduced patient survival in several solid neoplasms. 73 , 74 , 75 , 76 Interestingly, in the case of PDAC, the amount of IgG4 in intratumor but not those in the peritumor areas correlated with reduced survival. 76 Several mechanisms may account for the tumor-promoting functions of IgG4, such as competition between IgG4 and IgG1 for binding to cancer antigens or to Fc receptors of immune effector cells with reduced functional activity.…”

Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression

“…The authors also noted IgG4 + cell levels correlating to gross tumor appearance, tumor depth, lymph node metastasis, venous invasion, and lymphatic invasion [36]. Similarly, higher IgG4 levels in the serum and higher IgG4/IgE ratios were observed in patients with metastatic colorectal cancer than non-metastatic patients [37]. Tissue samples from these patients indicated that IgG4 was found very near to macrophages and that IgG4s were inducing these macrophages to express cell surface and secretory markers characteristic of an immune-suppressive state that could promote a pro-tumorigenic microenvironment.…”

Prognostic analysis of cuproptosis-related gene in triple-negative breast cancer

“…Moreover, a high abundance of regulatory T cells is significantly associated with high tumor expression levels of immune checkpoint inhibitor genes ( 44 , 45 ), which may explain the effective response of the low CRG_score group to immunotherapy. Although the presence of B cells and plasma cells is a good predictor of patient prognosis ( 46 , 47 ), B cells also have immunosuppressive roles in TNBC by enhancing the levels of myeloid-derived suppressor cells (MDSCs) or promoting IL-10 levels to facilitate isotype conversion to immunosuppressive IgG4 antibodies ( 48 , 49 ). In fact, the effects of the humoral immune response on tumors may not be related to the presence of B cells ( 50 ), but rather depend on the tumor antigen recognition ability and activation of the complement signaling pathway, which ultimately determines the immune phenotype of B cells.…”