Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer

Abstract

In immune system, B cells are classically positive modulators that regulate inflammation and immune responses. Regulatory B cells (Bregs) are a subset of B cells which play crucial roles in various conditions, including infection, allergies, autoimmune diseases, transplantation, and tumors. Until now, unequivocal surface markers for Bregs still lack consensus, although numerous Breg subsets have been identified. Generally, Bregs exert their immunoregulatory functions mainly through cytokine secretion and intercellular contact. In the tumor microenvironment, Bregs suppress effector T cells, induce regulatory T cells and target other tumor-infiltrating immune cells, such as myeloidderived suppressor cells, natural killer cells and macrophages, to hamper anti-tumor immunity. Meanwhile, the cross-regulations between Bregs and tumor cells often result in tumor escape from immunosurveillance. In addition, accumulating evidence suggests that Bregs are closely associated with many clinicopathological factors of cancer patients and might be potential biomarkers for accessing patient survival. Thus, Bregs are potential therapeutic targets for future immunotherapy in cancer patients. In this review, we will discuss the phenotypes, functions, and clinical relevance of Bregs in cancer.

IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

“…B cells also exhibit distinct phenotypes under different TME conditions, with Bregs being a recently identified B cell subtype exhibiting immunosuppressive functions (60,61). Much like Tregs, Breg recruitment can result in the modulation of local cellular responses through the production of IL-35 and other regulatory cytokines (62). In mouse models of breast cancer, Bregs induce T cell differentiation into Tregs and thereby accelerate tumor growth and lung metastasis (63).…”

“…As a specific B cell subtype, i35-Bregs can regulate other stromal cells within the TME including effector T cells, tumor-infiltrating MDSCs, NK cells, and macrophages (35,37). As the specific molecular markers of Bregs are unclear, however, future in-depth analyses of IL-35 and Bregs are required to understand the immunological effects of i35-Bregs (37,62).…”

Tertiary Lymphoid Structures as a Predictive Biomarker of Response to Cancer Immunotherapies

“…Additionally, B cells secrete a wide range of cytokines, which have potential to influence multiple cell types, including T cells, NK cells and myeloid cells. This includes, again, cytokines with anti-tumoral effects [such as IL-6, IL-12, IL-13, TNF-α and IFN-γ ( 43 )] as well as pro-tumoral character [such as IL-10, IL-35 and TGF-β ( 44 )]. Regulatory B cell subsets (Bregs) which play a tumour-promoting role have also been identified in tumours ( 45 , 46 ).…”

Transforming growth factor‐beta1 and myeloid‐derived suppressor cells: A cancerous partnership

“…Consequently, Bregs suppress the tumor immune response and promote tumor growth and progression. 8,14 For instance, MDSCs promote Bregs and suppress overall B cell function by IL-10 and TGF-β1 secretion, 131,209 and in a 4T1 breast cancer model, MDSCs induce PD-L1-expressing Bregs that inhibit T-cell function and induce T cell apoptosis. 210 As mentioned above, Bregs also educate MDSCs through TGF-β1 signaling, 139 which suggests a putative positive interaction between both types of cancer cells.…”

“…Among immune cells that may have an intimate interplay with TGF-β1 to establish an immunosuppressive TME, MDSCs have attracted great interest due to their role in several pathological conditions, including cancer. 7,8 MDSCs are one of the main orchestrators of cancer-related inflammation; they express different polarized features that contribute to the inflammatory milieu within TME and promote cancer cell outgrowth. Immunosuppressive MDSCs function relies on the cancer subversion of the immune surveillance by repressing T-celldependent immunity.…”