Tumor-Draining Lymph Node Reconstruction Promotes B Cell Activation During E0771 Mouse Breast Cancer Growth

Abstract

Lymph node metastasis is associated with tumor aggressiveness and poor prognosis in patients. Despite its significance in cancer progression, how immune cells in the tumor-draining lymph node (TDLN) participate in cancer immune regulation remains poorly understood. It has been reported that both anti-tumor and exhausted tumor-specific T cells can be induced in the TDLNs; however, B cell activation and maturation in the TDLN has received far less attention. In our studies using C57BL/6 mouse syngeneic E0771 breast cancer or B16F10 melanoma cell lines, tumor-associated antigens were found colocalized with the follicular dendritic cells (FDCs) in the germinal centers (GCs), where antigen-specific B cell maturation occurs. LN conduits and the subcapsular sinus (SCS) macrophages are two major routes of antigen trafficking to FDCs. Tumor growth induced LN conduit expansion in the B cell zone and disrupted the SCS macrophage layer, facilitating both the entry of tumor-associated antigens into the B cell zone and access to FDCs located in the GCs. Regional delivery of clodronate liposome specifically depleted SCS macrophages in the TDLN, increasing GC formation, and promoting tumor growth. Our study suggests that TDLN reconstruction creates a niche that favors B cell activation and maturation during tumor growth.

Dynamic changes in B cell subpopulations in response to triple-negative breast cancer development

“…In a recent study, authors demonstrated that tDLNs from E0771 tumor-bearing mice undergo an intense morphological change following tumoral implantation. According to Louie et al tumor growth leads to the expansion of LN conduits in the B cell zone and disruption of the sub-capsular sinus (SCS) macrophage layer, favoring the transport of TAAs to GC zones and associated follicular dendritic cells (FDCs) 65 . Despite not assessing the kinetics of distinct B cell subsets through the weeks of tumor development, Louie et al reported the appearance of GC B cells in the tDLNs of the E0771 model as early as 7 days post-tumor implantation, indicating activation and proliferation of B cells in this site.…”

Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment

“…While T cell-mediated immune response within TDLNs has received more attention, the role of B cells remains poorly understood. Nevertheless, a recent study conducted by Louie and colleagues has established a connection between tumor antigen-specific B cell maturation and tumor growth ( 205 ). Using B16F10 melanoma cells and a mouse model of breast cancer, the authors reported that tumors reconstructed TDLNs by disruption of the subcapsular sinus macrophage layer, which is a route for antigens to enter the germinal centers (GCs).…”

“…Using B16F10 melanoma cells and a mouse model of breast cancer, the authors reported that tumors reconstructed TDLNs by disruption of the subcapsular sinus macrophage layer, which is a route for antigens to enter the germinal centers (GCs). Consequent entry of tumor-associated antigens into the GCs promoted B cell activation and maturation, which positively correlated with tumor growth and metastasis ( 205 ). While the role of B cells in cancer immunity remains controversial, this study highlights the connection between tumor progression in TDLNs and B cell activity, shedding light on future studies that may contribute to a deeper understanding of immunity within TDLNs and to the development of cancer immunotherapies.…”

“…In fact, recent findings have provided insight into how cytotoxic (CD8 + ) T cells interact with LECs in the TME, showing a dose-dependent effect of T cells on the immune response. Garnier et al showed that, while IFN-g released by T cells initially induced LV immunosuppression, elevated T cell densities eventually dampened this effect and induced LEC apoptosis (204). At higher T cell densities, IFN-g stimulated the cross-presentation of tumor antigens by LECs following T cellmediated tumor death, which subsequently lead to LEC apoptosis and reduction of tumor-associated LV density and metastasis (204).…”

“…Garnier et al showed that, while IFN-g released by T cells initially induced LV immunosuppression, elevated T cell densities eventually dampened this effect and induced LEC apoptosis (204). At higher T cell densities, IFN-g stimulated the cross-presentation of tumor antigens by LECs following T cellmediated tumor death, which subsequently lead to LEC apoptosis and reduction of tumor-associated LV density and metastasis (204). Although the mechanism underlying these findings remains to be further studied, these results offer an optimistic possibility to enhance anti-tumor T cell responses as a strategy to combat cancer.…”