Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment

Abstract

B cells are crucial component of humoral immunity, and their role in the tumor immune microenvironment (TME) has garnered significant attention in recent years. These cells hold great potential and application prospects in the field of tumor immunotherapy. Research has demonstrated that the TME can remodel various B cell functions, including proliferation, differentiation, antigen presentation, and antibody production, thereby invalidating the anti-tumor effects of B cells. Concurrently, numerous immune checkpoints (ICs) on the surface of B cells are upregulated. Aberrant B-cell IC signals not only impair the function of B cells themselves, but also modulate the tumor-killing effects of other immune cells, ultimately fostering an immunosuppressive TME and facilitating tumor immune escape. Blocking ICs on B cells is beneficial for reversing the immunosuppressive TME and restoring anti-tumor immune responses. In this paper, the intricate connection between B-cell ICs and the TME is delved into, emphasizing the critical role of targeting B-cell ICs in anti-tumor immunity, which may provide valuable insights for the future development of tumor immunotherapy based on B cells.

Keywords: B cell; antitumor immunity; immune checkpoint (IC); immune checkpoint inhibitor (ICI); tumor immune microenvironment (TME).

Figure 1

Dysfunction of B cells in the TME. A) Tumor cells block B cell proliferation by high expression of HLA‐G and predation of oxygen and glucose in the TME, and MSDCs can also inhibit B cell proliferation through specific molecules. B) Tumor cells can modulate specific immune pathways, causing B cells to differentiate into TIPBs, Bregs, and macrophage‐like cells, and these types of B cells are detrimental to anti‐tumor immune responses. C) Tumor cells and MDSCs upregulate ICs on the surface of B cells, while IL‐5 and oxidative stress in the TME promote the expression of inflammatory factors, such as IL‐6, IL‐10, and TGF‐β, in B cells, and these immunosuppressive molecules negatively regulate effector T cells and promote tumor progression. D) ICs upregulated in B cells can limit the activation, antigen presentation, and co‐stimulatory functions of B cells and affect the anti‐tumor effect of T cells. Moreover, antibodies in the TME can bind to tumor cells and macrophages, mast cells, etc. without being able to participate in the tumor killing effect. Abbreviations: TME, tumor immune microenvironment; IL, Interleukin; MDSC, myeloid‐derived suppressor cell; HLA, human histocompatibility leukocyte antigen; ILT2, immunoglobulin‐like transcript 2; iNOS, inducible nitric oxide synthase; ARG1, arginase 1; TIPB, tumor‐induced plasmablast‐like‐enriched B cell; IL, Interleukin; TGF‐β, transforming growth factor‐β; PPARα, peroxisome proliferator‐activated receptor α; Breg, regulatory B cell; TSLP, thymic stromal lymphopoietin; LTB4, leukotriene B4; TSLP, thymic stromal lymphopoietin; Mφ, Macrophage; TAM, tumor‐associated macrophage; BCR, B‐cell receptor; TAB, tumor‐associated B cell; IFN, interferon; ADO, adenosine; SHP‐2, src homology 2‐domain‐containing tyrosine phosphatase 2 to phosphotyrosine; ADCC, antibody‐dependent cell‐mediated cytotoxicity. This figure was created based on the tools provided by Biorender.com.

Figure 2

Mechanism of tumor immune response restriction by B cells with high IC expression. IC molecules such as TIM‐1, CTLA‐4, PD‐1, TIGIT, and other IC molecules highly expressed on the surface of B cells inhibit T cell proliferation and expression of IFN‐γ, and promote the exhaustion of T cells; B cells with upregulated expression of IC also regulate the functions of NK cells, MDSC, and Treg, and indirectly inhibit the anti‐tumor response. In addition, B cells with upregulated expression of IC express the immunosuppressive molecules IL‐10 and TGF‐β and act on T cells and other immune cells, which further enhance the inhibition of tumor killing. Abbreviations: MDSC, myeloid‐derived suppressor cell; BCR, B‐cell receptor; APC, antigen‐presenting cell; IL, Interleukin; TGF‐β, transforming growth factor‐β; Gra B, Granzyme B; NK, natural killer cell; IFN, interferon. This figure was created based on the tools provided by Biorender.com.

Figure 3

Comparison of B‐cell ICs and T‐cell ICs. B‐cell ICs and T‐cell ICs share similarities in that they are the same type of ICs and exhibit comparable actions. However, B‐cell ICs and T‐cell ICs differ in their specific functions and mechanisms of action. T‐cell ICs primarily influence the antitumor immune response mediated by T cells, while B‐cell ICs can additionally impact various B cell functions, such as the secretion of immunosuppressive molecules, antigen presentation, co‐stimulation, and the proliferation and activation of memory B cells. Consequently, T‐cell ICs are primarily involved in antitumor cellular immunity, while B‐cell ICs can also modulate humoral immunity. Furthermore, interactions may occur between IC ligands and receptors of different subpopulations of B cells and T cells. Abbreviations: IC, immune checkpoint; Treg, regulatory T cell; Tfh, T follicular helper cell. This figure was created based on the tools provided by Biorender.com.

Figure 4

B‐cell immune checkpoint blockade restores anti‐tumor immunity. Blockade of aberrant IC signaling on B cells may facilitate the restoration of B cell function while relieving the inhibitory effect of B cells on T cell effector function. The use of antibodies targeting IC molecules restores B‐cell proliferation, activation, antigen presentation, and co‐stimulatory functions, and may contribute to the activation of humoral immunity by B‐cell production of tumor‐specific antibodies. In addition, the anti‐tumor effector function of T cells is restored, as evidenced by increased T cell infiltration and production of more granzyme B and IFN‐γ, and enhanced tumor killing. Abbreviations: IC, immune checkpoint; IFN, interferon; APC, antigen‐presenting cell; MDSC, myeloid‐derived suppressor cell; Treg, regulatory T cell; Gra B, Granzyme B. This figure was created based on the tools provided by Biorender.com.

Figure 5

Potential strategies for B‐cell IC development. Starting from the identified tumor ICs of other immune cells, immune molecules, or surface markers abnormally expressed by B cells, the potential IC molecules of B cells are initially identified. The expression of this IC is determined using PT‐PCR. Afterward, the abnormal expression of this IC is blocked, and changes in tumor growth and immune infiltration are observed. Revealing the mechanism of the role of B‐cell IC in tumor immunity also requires further exploration of the effects of IC on B‐cell function and other immune cell functions. Finally, after obtaining relevant positive results in tumor animal models, the role of this IC in tumor progression is verified in clinical cohorts using relevant ICI. Abbreviations: IC, immune checkpoint. This figure was created based on the tools provided by Biorender.com.