What is the key role of tumor-infiltrating B lymphocytes in immunotherapy？

What is the key role of tumor-infiltrating B lymphocytes in immunotherapy？

What is the key role of tumor-infiltrating B lymphocytes in immunotherapy？  In clinical immunotherapy, patient stratification and response assessment are mainly focused on T cells.

However, recent studies have also determined the key role of B lymphocytes in immunotherapy. Their presence is associated with different types of cancer and improved prognosis, including breast cancer, melanoma, renal cell carcinoma, hepatocellular carcinoma, and hepatocellular carcinoma. And head and neck squamous cell carcinoma. However, the tumor-promoting effect of Breg cells has also been widely reported.

Tumor infiltrating B cells mainly include: germinal center B cells, Naive B cells, plasma cells, etc. The specific markers are shown in the table below

Various types of tumor infiltrating B cells, such as activated B cells, can play an anti-tumor activity through antigen presentation and release of granzymes. Plasma cells can release antibodies and play anti-tumor activity through ADCC, CDC, etc.; regulatory B cells inhibit immunity by releasing VEGF, IL-10, etc., and promote angiogenesis to promote tumor development.

Tumor infiltrating B cells and their function (Reference 1)

Antigen presenting B cells

The characteristic of professional APCs is that they can take up antigens and load the processed antigen products onto MHC molecules and present them to T cells.

Decades ago, B cells were discovered to act as APCs, although they seem to be inferior to DCs (probably because of their reduced uptake of non-specific antigens). When B cells encounter antigens, their binding affinity is relatively high (multivalency), so B cells are more sensitive to lower concentrations of antigen.

Before immunization, antigen-specific B cells are very rare. Therefore, it has long been believed that B cells have the lowest contribution to activating Naive CD4 T cells.

In lung cancer patients, TIL-B cells affect the CD4 T cell phenotype. Specifically, activated TILB cells (CD69+HLA-DR+CD27+CD21+) are associated with CD4 effector T cell responses (CD4+IFNγ+), proving the role of B cells as promoting anti-tumor immune responses.

Antibody producing B cells (plasma cells)

Plasma cells are characterized by no CD20 expression, and co-expression of CD38, CD138, and CD79a. Plasma cells play an important role in promoting anti-tumor immunity.

CD8+TILs accompanied by CD20+B cells are more effective and can be further enhanced by stromal plasma cells.

In patients with high-grade severe ovarian cancer, infiltrating CD20+ B cells, CD4+ and CD8+ T cells, and plasma cells are associated with increased tumor survival rates, and 65% of patients survive 10 years after diagnosis.

The increased diversity of class-switched B cells and B cell receptors (BCR) is related to the activity of tumor-related germinal centers.

It is worth noting that some autoantibodies have also been found to promote tumor growth. Antibodies deposited on tumor sites in the form of immune complexes activate receptors through Fcγ, recruit myeloid cells and macrophages, secrete pro-angiogenic factors and immunomodulatory cytokines, and promote tumor progression.

Regulatory B cells

Regulatory B (Breg) cells are a subgroup of B cells that have their unique immunomodulatory and immunosuppressive properties, and play an important role in peripheral tolerance. Breg cells are associated with poorer clinical outcomes in cancer. In addition to IL-10 production, the phenotypic markers that characterize Breg cells have not yet been fully established.

Breg cells secrete IL-10, thereby inhibiting DC differentiation, inhibiting the proliferation of TH1 and TH17 cells, and inducing the differentiation of Treg cells. Breg suppression of immune function is beneficial to the treatment of autoimmune diseases, because the lack of Breg cells can lead to the deterioration of rheumatoid arthritis (RA) and systemic lupus erythematosus.

In cancer patients, Breg secretes IL-10, TGF-β, etc., which can inhibit the activation and proliferation of CD8+ T cells, and produce effect factors such as IFN-γ, TNF-α, and granzyme B.

This indicates that B cells have different functions depending on their location. Simple B cells may differentiate into Breg phenotypes in the immunosuppressive tumor microenvironment (TME).

B cell-based tumor immunotherapy

Activate conventional B cells

Through B cell ligands (such as CpG) to activate B cells, increase the secretion of antibodies, and lyse tumors.

Clear regulatory B cells

Regulatory B cells secrete inhibitory cytokines such as IL-10 to inhibit tumor immunity. Clearing regulatory B cells with CD20 antibodies is a strategy

Cell therapy to activate B cells

Mainly the above three types of strategies, but they are all in the early stage.

Brief comments:

B cells themselves are not strong, so tumor research pays little attention to B cells. More attention is paid to effector cells (such as T cells and NK). However, B cells, especially regulatory B cells, inhibit tumor immune activity and even weaken the anti-tumor activity of PD-1 inhibitors, which has begun to attract attention.

(source:internet, reference only)

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