IgG4-Mediated M2 Macrophage Polarization in Tertiary Lymphoid Structures of Esophageal Cancer: Implications for Immunosuppression

Background: Our previous research highlighted the potential role of immunoglobulin G4 (IgG4) in mediating immunosuppression within the tumor microenvironment (TME). Tertiary lymphoid structures (TLS) in the TME have important immune-related functions. This study aims to analyze the distribution characteristics of IgG4-expressing cells, regulatory T cells (Tregs), and M2-type macrophages as well as to elucidate the relationship between IgG4 and the polarization of M2 macrophages within TLS in esophageal cancer. Object: To elucidate the distribution of IgG4, Treg cells, and M2 macrophages in TLS and to assess the impact of IgG4 on macrophage polarization. Methods: Esophageal cancer tissue were analyzed with multiplex immunofluorescence to determine the spatial distribution and density of B cells, T cells, and their subtypes. The relationship between IgG4 and CD8+ T cells in TLS, along with interleukin-10 (IL-10) expression and Treg presence, was studied. Serum IgG4 and IL-10 levels were compared between patients and healthy controls. In vitro, the impact of IgG4 on monocyte differentiation into M2 macrophages was observed. Results: IgG4 density was inversely related with CD8+ T cells in mature TLS tumor microenvironment 删除[王大海]: 字体: (默认)Times New Roman Italic, 倾斜 设置格式[王大海]: indicating a potential immunosuppressive role (P<0.05,*). Serum analysis revealed that both IgG4 (P<0.01, **) and IL-10 (P<0.0001, ****) were significantly elevated and positively correlated in tumor patients compared to controls (P<0.01, **). In vitro experiments confirmed that IgG4 monocyte differentiation into M2 macrophages, potentially enhancing the immunosuppressive phenotype in TLS. Conclusion: IgG4 and IL-10 may contribute to immunosuppression in esophageal cancer by promoting the polarization of M2 macrophages within TLS, which could be a therapeutic target. are known to form in settings of 删除[慧 王]: ing 删除[慧 王]: In recent years, tumor TLStertiary lymphoid structures have received increasing attention, The presence and composition of TLS within tumors have been increasingly recognized as pivotal determinants of the TME's immunological profile and as predictive markers for patient prognosis. Several studies have correlated the density of TLS and immune cell infiltrates, such as CD20+ B cells, with improved clinical outcomes in various malignancies, 删除[慧 王]: tertiary lymphoid structures ( 删除[王大海]: