Multifaceted function of B cells in tumorigenesis

Abstract

B lymphocytes (B cells) play a complex and paradoxical role in tumorigenesis. They can recognize tumor-associated antigens, present these antigens to T cells, and produce antibodies that directly target and eliminate tumor cells. This makes B cells a potentially powerful ally in combating cancer. However, B cells also exhibit immunosuppressive functions, secreting cytokines like IL-10 or generating tumor-promoting antibodies that dampen the anti-tumor immune response, and some tumor cells have even been shown to exploit B cells to promote their growth and metastasis. This dual nature of B cells presents both opportunities and challenges for tumor immunotherapy. In this review, we summarize the mechanisms underlying the multifaceted functions of B cells and their current applications in cancer immunotherapy. Furthermore, we also explore the key issues and future directions in this field, emphasizing the need for further research to fully harness the anti-tumor potential of B cells in the fight against cancer.

Keywords

B cells / anti-tumor / pro-tumor / B cell-targeted immunotherapy

1 Introduction

The tumor microenvironment (TME) is a complex and dynamic ecosystem, populated by a diverse array of immune cells that play critical functions in shaping cancer progression. In recent years, there has been an intensive focus on understanding the heterogeneous functions of tumor-infiltrating T cells and their potential as targets for immunotherapy [1]. The remarkable progress in cancer immunotherapy over the past decade has been largely driven by targeting T cell-based immune checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) [2]. The approval and clinical success of immune checkpoint inhibitors (ICIs), which unleash the anti-tumor potential of T cells, have revolutionized the treatment landscape for numerous cancer types [3]. However, the functions of another key player in adaptive immunity B cells, have remained relatively understudied in comparison.

While the pro-tumor and anti-tumor functions of tumor-infiltrating T cells have been extensively characterized, the multifaceted functions of B cells in the TME warrant deeper exploration (Fig.1). The multifaceted functions of B cells in tumor immunology highlight the complexity of the TME and the need for a nuanced understanding of the diverse immune cell populations involved. B cells, including regulatory B cells (Bregs), inflammatory B cells, and antigen-presenting B cells, are capable of secreting cytokines, generating tumor-promoting antibodies or inducing T cell tolerance, thereby facilitating tumor growth. However, the presence of B cells in tertiary lymphoid structures (TLS) contributes to effective anti-tumor immunity, potentially tipping the balance toward a more favorable anti-tumor immune landscape. Harnessing the anti-tumor potential of B cells, while mitigating their pro-tumor functions is a promising avenue for developing novel cancer immunotherapies.

This review aims to provide a comprehensive overview of the current understanding of the multifaceted functions of B cells in tumor immunology. By exploring the mechanisms underlying their anti-tumor and pro-tumor functions, we aim to emphasize the significance of B cells as important, yet often overlooked, contributors to the complex landscape of the TME. Unraveling the nuances of B cell biology in the context of cancer paves the way for developing more targeted and personalized immunotherapeutic approaches, ultimately improving patient outcomes.

2 Anti-tumor function of B Cells

The anti-tumor functions of B cells includes the formation of TLS in tumor, production of tumor-specific antibodies, activation of the complement system, antigen presentation, cytokine production [4]. B cells produce tumor-specific antibodies that bind to and opsonize tumor cells, marking them for destruction by other immune cells, such as natural killer (NK) cells and macrophages. The mechanisms of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), mediated by these effector cells, lead to the direct killing of opsonized tumor cells [5]. In addition, the complement-dependent cytotoxicity (CDC) pathway is an important anti-tumor mechanism facilitated by B cell-derived antibodies [6]. Tumor-specific antibodies produced by B cells also activate the complement system, leading to the formation of the membrane attack complex (MAC) and subsequent lysis of tumor cells. Furthermore, B cells act as professional antigen-presenting cells (APCs) and present tumor-associated antigens (TAAs) to CD4⁺ and CD8⁺ T cells, thereby facilitating their activation and expansion. This crosstalk between B cells and T cells enhances the overall anti-tumor immune response [7]. In addition, B cells secrete various cytokines and chemokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and C-X-C motif chemokine ligand 13 (CXCL13), which exert direct anti-tumor effects or indirectly promote the recruitment and activation of other anti-tumor immune cells including T cells and NK cells [8]. These diverse anti-tumor effector functions of B cells highlight their multifaceted function in cancer immunology, extending beyond their contribution to the formation and function of TLS. Understanding and harnessing these various mechanisms could lead to the development of novel B cell-based immunotherapies for cancer treatment.

2.1 B cells in TLS

Numerous clinical cohort studies have demonstrated that B cell infiltration and the formation of TLS are positively correlated with patient response to immunotherapy in many different tumor types [9]. TLS formation is associated with improved survival and a “hot” TME in several cancer types [10]. TLS are ectopic lymphoid-like structures resembling secondary lymphoid organs, such as lymph nodes, and are characterized by the presence of B cells, T cells, and other immune cells [11]. The mature TLS are enriched with a large number of B cells. These B cell clones are selectively activated and expanded, undergoing antibody class switching and somatic hypermutation. Subsequently, these B cells proliferate and differentiate into plasma cells capable of producing immunoglobulin G (IgG) antibodies targeting TAAs. In addition, B cells within TLS secrete cytokines and chemokines more efficiently, facilitating the activation of NK cells and macrophages, as well as the proliferation of tumor-specific T cells [12]. Studies have demonstrated that the presence of B cells and TLS within the TME of metastatic melanoma and renal cell carcinoma patients is positively associated with improved responses to immunotherapy [13]. Additionally, the presence of B cells in clinical cohorts of soft tissue has been linked to improved patient prognosis and enhanced responses to immunotherapy [14]. These studies have highlighted the critical function of B cells and TLS in anti-tumor immunity, providing new strategies and insights for tumor immunotherapy.

2.2 Tumor-infiltrating B cells (TIL-Bs)

Driven by recent advances in single-cell sequencing, TIL-Bs have emerged as critical regulators in various solid tumor types, impacting both tumor progression and the response to ICIs. TIL-Bs are localized in at least three distinct structural regions of TME: highly organized TLS, lymphangioleiomyomatosis (LMA), and intraepithelial infiltrates. In highly immunogenic “hot” tumors, TIL-Bs often greatly exceeds those of B cells in healthy non-lymphoid tissue. Similar to T cells, TIL-Bs including plasma cells are associated with favorable prognoses in most cancers [15].

A recent study revealed that TIL-Bs, after further clustering, are closely related to the efficacy of immunotherapy in follicular B cells [16]. The latest article reported that the differentiation of tumor-infiltrating plasma cells primarily occurs through two distinct pathways: germinal center (GC) and extrafollicular (EF) responses, with notable preferences for specific cancer types. For instance, liver cancer is predominantly driven by the EF response, whereas colorectal cancer (CRC) is primarily driven by GC response [17]. In addition, it has been reported that the density of TIL-Bs correlates with T cell infiltration to hepatocellular carcinoma (HCC), as well as T cell and NK cell activation, leading to decreased tumor cell viability [18]. TIL-Bs significantly enhance the prognostic impact of CD4⁺ and CD8⁺ TILs, an effect that is particularly pronounced in tumors containing TLS [19]. Moreover, costimulatory molecules, such as CD27 and CD40, expressed on both T cells and B cells are associated with improved patient survival in HCC [20]. However, TIL-Bs also showed the opposite trend in certain tumor types. For details, see Tab.1.

2.3 The mechanism of B cells in anti-tumor effect

2.3.1 Secreting antibodies

While the majority of self-reactive B cells are eliminated through central tolerance mechanisms, a subset escapes this process and persist in the peripheral circulation. In healthy individuals, these self-reactive B cells constitute roughly 20% of the total population of circulating naive mature B cells [21]. Typically, these B cells are regulated by peripheral tolerance mechanisms. However, if this tolerance is breached, self-reactive B cells may become activated and infiltrate GCs, where they undergo somatic hypermutation and class-switching. The presence of autoantibodies in cancer patients suggests a breakdown in self-tolerance, similar to what is observed in autoimmune disorders [22]. Recent studies have demonstrated that TIL-B-derived tumor-reactive autoantibodies, which target the surface of tumor cells, either occur naturally or develop through antigen-driven selection [23]. More compelling evidence suggests that the hIgG1-G396R homozygous genotype independently serves as a protective prognostic factor for survival in CRC patients, based on a fluid-regulation analysis of a cohort exceeding 1000 individuals with 10 years of follow-up data. In a mouse model of 4T1 breast cancer in situ implantation, it was observed that the proportion and number of B cells in the draining lymph node (DLN) increased significantly before tumor metastasis [24]. The capacity of tumor-educated B cells to produce antibodies, particularly IgG, was notably enhanced, leading to a significant elevation of IgG levels in the serum of selectively targeted tumor-bearing mice [5]. These disease-specific antibodies were able to selectively target tumor membrane antigens. In vivo functional experiments have validated that depletion of B cells resulted in a substantial reduction in lymph node metastasis and prolonged survival period among tumor-bearing mice. Conversely, the administration of pathological antibodies led to a significant increase in lymph node metastasis [25]. Although serological screening methods have been utilized for decades to identify antigens recognized by serum antibodies [26], identifying the target antigens of TIL-B-derived antibodies is more technically challenging, with only 70 identified to date [8]. These antigens primarily originate from intracellular proteins, rather than membrane-bound or secreted proteins, lipids, or nucleic acids [27,28].

Antibodies are capable of initiating potent innate effector mechanisms, such as CDC, ADCP, and ADCC. There is increasing evidence that these mechanisms are relevant to TIL-B-derived antibodies in cancer. The complement system consists of plasma proteins that interact to opsonize pathogens, triggering a cascade of inflammatory responses. These responses assist immune cells in combating infections and tumors, and maintaining homeostasis [29]. CDC is initiated when membrane-bound antibodies bind to the C1q molecule, which, along with C1r and C1s, forms the C1 complex—the first component in this cascade. Activation of the C1 complex triggers a series of enzymatic events, leading to the covalent deposition of opsonins on target cells, as well as the generation of potent chemoattractants, anaphylatoxins, and MAC [30]. Importantly, IgG antibodies bound to cell surface antigens form ordered hexamers, creating high-affinity docking sites for C1 binding and subsequent activation of the classical complement pathway [31]. Introducing mutations to enhance hexamerization via Fc-mediated clustering boosts the tumor therapeutic efficacy of IgG1 monoclonal antibodies (mAbs) by increasing CDC activity [32]. This innovative approach is emerging as a novel strategy for utilizing antibodies to engage complement in anticancer therapy. For instance, the introduction of an hexamerization-enhancing mutation into CD20 and CD37 mAbs led to a remarkable enhancement in CDC activity observed in primary lymphocytic leukemia (CLL) samples [33].

In human ovarian cancer, TIL-B-derived IgGs targeting matrix metallopeptidase 14 (MMP14) were demonstrated to stimulate ADCP via THP-1 monocytes in vitro, initiated by the interaction between antibody-antigen complexes and Fc receptors on myeloid cells, ultimately leading to phagocytosis of the target cells [24]. Similarly, in a murine CRC model, tumor-infiltrating macrophages were observed to engulf tumor cells in vivo when exposed to anti-tumor IgG. Additionally, in vitro studies demonstrated that the uptake of immune complexes by dendritic cells (DCs) effectively initiates anti-tumor T cell responses [5]. Macrophages and NK cells serve as the primary executors of ADCC, a process wherein effector cells equipped with Fc receptors identify and eliminate target cells coated with antibodies, displaying tumor- or pathogen-derived antigens on their surfaces [34]. However, there is indirect evidence suggesting that antibodies derived from TIL-Bs initiate ADCC. In renal cell cancer, tumors with a higher proportion of IgG-stained cells exhibited greater infiltration by CD68⁺ macrophages compared to tumors characterized by high apoptotic cell counts but low levels of IgG-stained cells. Furthermore, a close spatial relationship between macrophages and IgG-stained tumor cells was noted [12]. An additional study revealed that in prostate cancer tumors, elevated levels of plasma cell infiltration, IgG expression, and NK cell activity were associated with extended metastasis-free survival and disease-free survival (DFS). This association may signify augmented ADCC [35]. Furthermore, after Bregs depletion, the ADCC ability of peripheral blood mononuclear cells (PBMCs) was enhanced in vitro [36]. In the future, relevant methods need to be established for directly measuring ADCC in vivo (Fig.2).

2.3.2 Functions to tuning T cell activation and differentiation

TIL-Bs promoted the function of T cells either by producing cytokines or by serving as APC to interact with T cells. Metastatic ovarian tumors exhibited TIL-Bs secreting granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, and IL-12p40, which possess the capacity to activate macrophages, DCs, T cells, and NK cells. This led to enhanced recruitment of DCs to TLS and augmented antigen-presenting capabilities, contributing to an improved anti-tumor immune response [37]. Through single-cell RNA sequencing (scRNA-seq), it was discovered that plasmablast-like TIL-Bs from ovarian cancer and melanoma patients exhibited elevated expression of transcripts encoding IFN-γ and chemokines known to attract T cells, macrophages, and NK cells, such as C-C motif chemokine ligand 3(CCL3), CCL4, and CCL5, in comparison to other TIL-B subsets. This observation correlated with increased infiltration of T cells [38]. In addition, intratumoral B cells support an anti-tumor immune response through several mechanisms, such as antigen presentation to T cells [39]. T follicular helper (Tfh)-like CD4⁺ T cells correlate with B cell infiltration and co-localize with B cells in melanoma [40], and in a mouse lung cancer model, inhibiting the formation of the TLS by Tfh or B cell depletion promotes tumor growth [41], these results indicate T-B cell interactions and TLS formation promote anti-tumor immunity. Consistent with these observations, the enrichment of Tfh cell transcriptional signature is associated with the GC B cell signature and prolonged survival in patients with lung adenocarcinoma (LUAD). Additionally, in a mouse model, the interactions between tumor-specific Tfh and GC B cells, along with IL-21 primarily produced by Tfh cells, are crucial for tumor control and the function of effector CD8⁺ T cells [39]. Besides presentation via MHC class II, antigen presentation via MHC class I may also be relevant. In oropharyngeal squamous cell carcinoma, a high abundance of TIL-Bs and a high density of direct interactions between B cells and CD8⁺ T cells within the TME have been associated with an excellent prognosis. This suggests that these patients may benefit from less intensive treatment approaches [42]. Furthermore, B cells enhance antigen presentation indirectly by secreting antibodies and forming immune complexes with antigens. Compared to antigens alone, IgG-complexed antigens not only bolstered DCs maturation but also facilitated the presentation of peptides via MHC class I and class II molecules. This process is anticipated to more effectively prime DCs for the activation of both CD4⁺ helper T cells and CD8⁺ cytotoxic T lymphocytes (CTLs) in vivo [43]. In another CRC model, increased antibody production indeed promoted antigen cross presentation via the immune complex, thereby enhancing anti-tumor function [5] (Fig.2).

2.3.3 Direct cytotoxicity

Granzyme B (GrB), a member of the serine protease family, is a major killer molecule produced by CTLs and NK cells. The expression of GrB in B cells correlates with the presence of “killer B cells,” which exhibit cytolytic activity against tumor cells in vitro [44]. Although GrB-secreting B cells did not express perforin, they were able to effectively induce apoptosis by secreting GrB. In another study, single-cell sequencing detected GrB⁺ B cells, which were associated with prognosis in patients with intrahepatic cholangiocarcinoma. Given that few reports demonstrated this B cell phenotype, further research are needed to explore the existence and function of GrB⁺ B cells in different patient samples. Besides the expression of GrB, B cells employ other killing mechanisms, such as the fas cell surface death receptor (Fas) ligand and tumor necrosis factor superfamily (TNFSF) members [44,45]. In contrast to B cells isolated from peripheral blood, which induce apoptosis and effectively eliminate various types of leukemia and solid tumor cells, B cells derived from head and neck squamous cell carcinoma patients exhibit diminished expression of TNFSF ligands and reduced cytotoxicity [44]. Recently, through single-cell integration analysis of pan-cancer species, the researchers identified two subgroups of B cells that are widespread at the pan-cancer level and enriched in tumors, both of which have prognostic potential: stress-response memory B cells and tumor-associated atypical B cells (TAAB), which were associated with shorter and longer survival in cancer patients, respectively [46]. Further investigation is needed to elucidate the detailed mechanisms behind the upregulation of B cell killing abilities (Fig.2).

3 Pro-tumor function of B Cells

Traditionally, B cells have been recognized as crucial components of the adaptive immune system, primarily tasked with generating antibodies to combat pathogens. However, recent research has unveiled a more intricate function for B cells in the TME, where they exhibit both anti-tumor and pro-tumor activities. A subset of B cells, known as Bregs, has been identified as playing a pro-tumor function in the TME. Several molecular markers are used to identify and characterize Bregs. For instance, CD19⁺CD24^hiCD38^hi cells are one of the most well-established phenotypic markers for identifying human Bregs. This subset has been shown potent immunosuppressive functions in gastric cancer [47], pancreatic ductal cancer [48] and head-and-neck squamous cell carcinoma [49]. Additionally, CD19⁺CD5⁺CD1d^hi cells are commonly used to identify murine Breg populations and were also found in human cervical cancer patients [50]. These CD19⁺CD5⁺CD1d^hi B cells produce high levels of IL-10, a key cytokine mediating their regulatory functions. It is important to note that the specific Breg markers may vary depending on the species, tissue, and disease context. Unlike regulatory T cells (Tregs), which have Foxp3 as their master transcription factor, Bregs have no well-identified lineage-defining transcription factors [7]. Moreover, Bregs do not neatly fit into the traditional B cell developmental subsets of naive, memory, or antibody-secreting cells (ASCs). Instead, they exhibit characteristics that resemble a combination of these different B cell subpopulations. Therefore, Bregs may not represent a distinct lineage of B cells, but rather a cell state that manifests an immunosuppressive phenotype under certain conditions [7].

Next, we will focus on the functions and mechanisms of B cells, particularly Bregs, in tumor promotion. In a mouse model of highly aggressive 4T1 breast cancer, the metastatic spread of the tumor cells was prevented by inactivating the tumor-associated Bregs [51]. Bregs contribute to tumor immune evasion and facilitate tumor growth and metastasis by producing tumor-promoting antibodies directly, secreting immunosuppressive cytokines and chemokines, suppressing the activity of other immune cell types, and regulating immune checkpoint molecules. Firstly, Bregs directly enhance tumor growth and survival by producing specific antibodies. Secondly, Bregs produce immunosuppressive cytokines, including IL-10, transforming growth factor-beta (TGF-β), IL-6, and TNF-α, which have direct pro-proliferative and anti-apoptotic effects on tumor cells, promoting their survival and growth [52]. These cytokines also indirectly support the tumor by inducing the recruitment and activation of other immunosuppressive cell types, such as myeloid-derived suppressor cells (MDSCs) and Tregs, further dampening the anti-tumor immune response [53–55]. Moreover, Bregs produce chemokines that directly promote tumor growth and angiogenesis. For instance, Bregs have been shown to secrete vascular endothelial growth factor (VEGF), which stimulates the formation of new blood vessels to supply the growing tumor with oxygen and nutrients [56]. This process of tumor angiogenesis is crucial for the continued expansion and metastasis of the cancer. Thirdly, Bregs induce the expansion of other immunosuppressive cell types, such as MDSCs and Tregs, further enhancing the pro-tumor environment [53]. Additionally, Bregs facilitate the establishment of an immunosuppressive TME through the production of immune checkpoint molecules, such as PD-L1. By expressing these inhibitory ligands, Bregs suppress the cytotoxic functions of T cells and NK cells, allowing the tumor to evade immune detection and elimination [57]. In the following sections, we will delve into the specific mechanisms by which Bregs operate in the TME, highlighting their critical function in tumor immune escape (Fig.3).

3.1 Production of tumor-promoting antibodies

Bregs directly increase tumor growth and survival by producing specific antibodies [25]. These antibodies bind to antigens on the surface of tumor cells, thereby activating the complement system. In certain cases, this activation triggers chronic inflammatory responses, leading to the secretion of various pro-inflammatory cytokines and growth factors that alter the TME and further support tumor growth and progression [58,59]. Furthermore, autoantibodies, under certain circumstances, enhance tumor cell proliferation and metastatic potential. For instance, autoantibodies detected in some cancer patients directly promote tumor cell proliferation and migration by activating receptors or signaling pathways on the surface of tumor cells. Studies have demonstrated the significant function of tumor-promoting antibodies in various cancers. For example, in breast cancer and gastric cancer, high levels of autoantibodies have been detected, binding to antigens on the surface of tumor cells and activating the complement system and pro-inflammatory responses, thereby promoting tumor growth and metastasis [25,60]. In summary, B cells, through the production of tumor-promoting antibodies, further support tumor growth and progression (Fig.3).

3.2 Secretion of immunosuppressive cytokines and chemokines

Bregs exert significant immunomodulatory effects in the TME by secreting a plethora of immunosuppressive cytokines, notably IL-10 and TGF-β. IL-10, a potent anti-inflammatory cytokine, suppresses the function of various immune cells, including effector T cells (Teffs), NK cells, and APCs [58,59,61]. In addition, Teffs are the primary executors of tumor immune surveillance, directly killing tumor cells by secreting cytotoxic molecules such as perforin and GrB. However, Bregs, through the secretion of IL-10 and TGF-β, suppress Teffs activation and cytotoxicity, thereby weakening the host’s immune response against the tumor [50,62]. Among them, IL-10 suppresses Teffs proliferation and IFN-γ production, reducing their anti-tumor effects. TGF-β further inhibits Teffs anti-tumor activity by modulating their differentiation and function [61]. This direct inhibitory effect makes Bregs play a crucial role in tumor immune escape.

In addition, Bregs secrete the chemokine CXCL13, which recruits tumor-associated Tregs to the TME [63]. These Tregs subsequently suppress the anti-tumor immune response. In experimental models of pulmonary metastasis, mice lacking the Cxcl13 gene exhibited fewer IL-10-producing B cells within the tumor immune microenvironment, compared to wild-type C57BL/6 mice. This reduction in Bregs enhanced the anti-tumor immune response in the Cxcl13-deficient mice [64]. However, it has also been shown that nanotrapping CXCL13 reduces Bregs in the TME and inhibits tumor growth [63].

Furthermore, Bregs in the TME also promote tumor angiogenesis by secreting pro-angiogenic factors, such as TGF-β and VEGF, providing tumor cells with necessary oxygen and nutrients to support their growth and dissemination [65]. Angiogenesis is a crucial process for tumor growth and metastasis, enabling tumors to acquire more nutrients and oxygen through the formation of new blood vessels, thereby sustaining their rapid proliferation and metastatic capacity. For instance, in breast cancer and lung cancer models, Bregs, by secreting TGF-β and VEGF, significantly promote tumor angiogenesis and growth, demonstrating the crucial function of Bregs in tumor angiogenesis [66,67] (Fig.3).

3.3 Modulation of other immunosuppressive cells

Bregs, through the secretion of IL-10 and TGF-β, induce the differentiation of CD4⁺ T cells into Tregs [47,68]. Tregs play a significant immunosuppressive role in the TME, directly inhibiting the activation and function of CD4⁺ Teffs by secreting inhibitory cytokines such as IL-10 and TGF-β [69]. In addition, Tregs suppress Teffs proliferation and cytotoxicity through direct cell–cell contact, thereby reducing their ability to kill tumor cells [50,62]. The accumulation of Tregs in the TME is considered a crucial mechanism of tumor immune escape. Beyond suppressing Teffs, Bregs further support tumor progression by modulating the functions of other immune cells. IL-10 secreted by Bregs induces macrophage polarization toward the M2 phenotype [52,70,71]. M2 macrophages exhibit immunosuppressive and pro-tumorigenic properties in the TME, inhibiting Teffs and promoting tumor angiogenesis and tissue remodeling through the secretion of factors such as IL-10, TGF-β, and VEGF [72].

Furthermore, Bregs suppress the maturation and antigen-presenting capacity of DCs through IL-10 [73]. DCs are potent APCs that activate naive T cells by capturing and presenting antigens, initiating an immune response. However, IL-10 diminishes DC maturation and function, reducing their antigen-presenting capacity, thereby decreasing T cell activation and weakening the host’s anti-tumor immune response (Fig.3).

3.4 Signaling malfunctions

Bregs facilitate the establishment of an immunosuppressive TME through the production of immune checkpoint molecules, such as PD-L1. Notably, PD-L1 expression in Bregs in the bone marrow and PBMC samples of acute myeloid leukemia patients was higher than that in samples from healthy donors [74]. Bregs induced by pancreatic cancer cell-derived IL-18 promote immune tolerance via the PD-1/PD-L1 pathway [75]. By expressing these inhibitory ligands, Bregs suppress the cytotoxic functions of T cells and NK cells, allowing the tumor to evade immune detection and elimination [57]. In addition, Bregs were found to promote the growth and invasiveness of HCC by directly interacting with liver cancer cells through the CD40/CD154 signaling pathway [76]. It is reported that Bregs in tumor tissues were significantly elevated compared to paracancerous tissues in various cancers, such as bladder cancer and gastric cancer [60,77]. Recent research has indicated that the stimulator of interferon genes (STING) agonist, cyclic GMP-AMP (cGAMP), induces IL-35 expression in B cells through an interferon regulatory factor 3 (IRF3)-dependent mechanism. Mechanistically, the STING-IL-35 axis in B cells inhibits NK cell proliferation and dampens the NK-driven anti-tumor response [78] (Fig.3).

4 B cells and tumor immunotherapy

4.1 B cells and ICIs

Indeed, several studies in human cancers have demonstrated a strong positive correlation between the infiltration of TIL-Bs or the presence of TLS and clinical response to immune checkpoint blockade [9,11,79]. In patients with non-small cell lung cancer (NSCLC), those who responded to nivolumab exhibited more TLS formation in their tumor tissues, accompanied by higher densities of plasma cell infiltration [80]. Preclinical studies have found that the combination of ICIs promotes B cell activation and antibody responses in mouse models of triple-negative breast cancer [81]. Similarly, in mouse models of lung cancer and CRC, anti-CTLA-4 antibodies increased the number of TILs infiltrating the tumor, ultimately leading to the induction of tumor-reactive antibodies and improved tumor prognosis [82,83]. In addition, previous studies have reported the presence of PD-1⁺ and PD-L1⁺ TIL-Bs in various human cancers [57,84,85], highlighting that the PD-1/PD-L1 axis has an inhibitory function in B cell-mediated anti-tumor responses. B cells interact with Tfh cells through the PD-1/PD-L1 pathway [86], and this interaction inhibits B cell activation and function by obstructing downstream signaling of the B cell receptor (BCR) [87,88]. Consequently, this reduces the necessary interactions between B cells and T cells, which are crucial for the expansion of CD4⁺ and CD8⁺ T cells driven by B cells [84]. Therefore, TIL-Bs may be directly influenced by PD-1 and/or PD-L1 immune checkpoint blockade. However, when applying ICIs, including anti-CTLA-4 [89] and anti-PD-1 mAbs [90–92], attention should be paid to the induction of autoreactive antibodies caused by enhanced GC reactions [93] and higher activation and proliferation of Tfh cells [90], which lead to B cell-derived therapeutic side effects, such as thyroid dysfunction or severe immune-related adverse events (irAEs) [90,92].

In addition, various checkpoint molecules expressed in B cells have been reported to play important intrinsic functions in B cell homeostasis and responses. For instance, T cell immunoreceptors with Ig and ITIM domains (TIGIT) expressed on memory B cells, inhibit T cell responses by suppressing the function of pro-inflammatory macrophages while promoting regulatory T cell function [94]. Lymphocyte activation gene-3 (LAG-3), along with other inhibitory receptors such as CD200 and PD-L1, is co-expressed on plasma cells. Upon TLR activation, these plasma cells express high levels of IL-10 and exert immunosuppressive effects [95]. However, in vivo experiments have shown that selective knockout of these surface molecules in B cell lineage does not inhibit tumor growth [96].

Conversely, the surface receptor T cell immunoglobulin and mucin domain 1 (TIM-1) has recently emerged as a promising marker for B cell regulation. In patients with systemic sclerosis, TIM-1 has been identified as a unique marker of the IL-10⁺ Breg subset [97]. TIM-1⁺ B cells are also highly enriched in IL-4 expression, promoting Th2 responses through the TIM-1/STAT3 axis [97,98]. Selective knockout of Havcr1 in B cells, the gene encoding TIM-1, significantly reduces tumor burden in a mouse melanoma model and enhances type 1 interferon response in B cells. Furthermore, the effective response to PD-1-targeted therapy is accompanied by a decrease in TIM-1⁺ TIL-B cells [96]. Therefore, TIM-1 is a promising therapeutic target that requires further preclinical and clinical research to provide stronger evidence for the development of specific antibodies or drugs.

4.2 B cell-based immunotherapy

With the rapid advancement of tumor immunology in recent years, the function of B cells in tumor biology has become increasingly clear, garnering significant attention and establishing them as highly promising targets for a new generation of cancer immunotherapy. Based on the function of B cells in tumor immunotherapy, a variety of B cell-based immunotherapies have emerged (Tab.2).

4.2.1 Monoclonal antibodies

mAbs have emerged as a crucial therapeutic modality for cancer, standing alongside surgery, conventional chemotherapy, and radiotherapy. Antibodies derived from TIL-Bs exert anti-tumor effects by inhibiting or degrading tumor antigens or by inducing ADCP/ADCC. Among them, rituximab, a humanized anti-CD20 mAb primarily used for B cell lymphoma, is currently in widespread clinical use. Additionally, developing neoantigens and designing mAbs with high specificity and low immunogenicity have consistently been a focus in tumor immunotherapy. In addition to traditional mAbs technologies, such as hybridoma and display technologies, the unique advantages of primary single B cell antibody screening technology have driven its rapid development. This approach, owing to the in vivo development and affinity maturation, exhibits notably high specificity and low immunogenicity [99]. It also ensures the native pairing of heavy chain (VH) and light chain (VL) chains. Moreover, primary single B cell antibody technology maximally preserves B cell diversity, allowing for the selection of antibodies with a broad range of specificities.

Beyond targeted engineering design of mAbs, the efficacy of antibody-based cancer therapies can be further enhanced by modifying the Fc domain of the antibody. Since these drugs mediate ADCC, ADCP, and CDC primarily through their Fc domain, modifications can improve binding to Fc receptors, enhance the recruitment of immune cells, and more effectively trigger innate effector mechanisms [100]. In contrast, the Fc-null of ICIs, such as anti-PD-1 and anti-CTLA-4 antibodies, are designed to avoid recruiting additional immune cells to prevent depletion of Teffs. However, our understanding of the mechanisms underlying antibody drugs remains incomplete, for example, studies have suggested that binding of anti-PD-1 antibodies to Fc receptors on M2-like macrophages may trigger hyperprogression in lung cancer patients [101]. Therefore, given the nascent understanding of the function of these mechanisms in anti-tumor immunity, careful consideration is required when modifying antibodies (Fig.4).

4.2.2 Activating B cells or enhancing their antigen-presenting capacity

Peptide or protein vaccines stimulate B cells to produce specific antibodies against cancer cells by introducing TAAs. For instance, the HER-2/neu vaccine using GM-CSF as an adjuvant effectively enhances the anti-HER-2/neu antibody response in breast cancer [102]. A Phase Ib clinical study demonstrated that a therapeutic B cell epitope vaccine could elicit a dose-dependent antibody response in HER-2⁺ gastroesophageal adenocarcinoma patients [103]. When adjuvants are used in combination with cancer vaccines, they significantly enhance B cell stimulation. For instance, CpG oligodeoxynucleotides (CpG-ODNs), recognized by Toll-like receptor 9 (TLR9) on B cells, significantly enhance ADCC in various cancers [104]. CpG also enhances the amplification of CD8⁺ T cells through empowering direct T–B interactions, demonstrating sustained anti-tumor efficacy after adoptive transfer [105]. Researchers have developed a TLR9 agonist-conjugated IL-12 Fc fusion protein that achieves effective tumor immunity by enhancing antigen presentation from B cells to T cells [106]. Additionally, monophosphoryl Lipid A (MLA) has been reported as an adjuvant to enhance antibody responses in various cancers [107].

Given the significant function of CD40 in B cell biology, the application of CD40 agonists enhances B cells-mediated T cell activation. In a mouse model of glioblastoma, vaccination with IFN-γ and CD40-activated 4-1BB⁺ B cells, combined with radiotherapy and PD-L1 inhibitors, promotes antigen cross-presentation and CD8⁺ T cell activation, significantly prolonging the survival of tumor-bearing mice [108]. Similarly, in a mouse mesothelioma model, treatment with low doses of anti-CD40 antibodies avoids the adverse effects of hyperimmune responses due to the overactivation of DCs [109]. Instead, it exerts effective anti-tumor effects by increasing the infiltration of B cells in tumors and DLNs [109] (Fig.4).

4.2.3 Breg depletion or inhibition

Given the dual function of B cells in tumor immunity, therapies targeting the depletion or inhibition of Bregs have garnered significant attention. Early studies have shown that B cell depletion achieves over 50% remission rates without side effects in limited CRC and metastatic melanoma patients using rituximab, leading to longer progression-free survival [110–112]. In a mouse pancreatic cancer model, the Bruton’s tyrosine kinase (BTK) inhibitor Ibrutinib limited the pro-tumor effects of B cells and tumor-suppressive macrophages [113]. Additionally, anti-CD20 mAbs inhibited the rapid progression of pancreatic cancer caused by Hif1a knockout [114].

However, the anti-tumor immunotherapy involving B cell depletion has been controversial. Some researchers argue that this approach is ineffective. In a mouse breast cancer model, anti-CD20 antibodies significantly promoted tumor growth and metastasis [51]. This phenomenon occurs because Bregs typically express low levels of CD20, and indiscriminately depleting B cells may inadvertently enrich the population of Bregs [51]. Compared to B cell depletion, selectively targeting Bregs using inhibitors of downstream signaling pathways to prevent their formation and enhance anti-tumor immunity has shown promise in mouse models [115–117]. Therefore, cautiously inhibiting or reprogramming Breg function and phenotype may be a more promising approach than B cell depletion (Fig.4).

5 Conclusions

B cells play a complex and multifaceted function in the tumor immunity process. B cells effectively recognize and bind to TAAs, becoming professional APCs that assist T cells in recognizing and killing tumor cells. However, the suppressive antibodies secreted by B cells may inhibit the anti-tumor immune response of T cells, and some tumor cells even exploit the cytokines and chemokines secreted by B cells to promote their growth and metastasis. Furthermore, abnormally activated B cells may also suppress the anti-tumor functions of other immune cells by secreting immunosuppressive cytokines such as IL-10. Therefore, B cells exhibit a duality in tumor immunity: they serve as powerful anti-tumor weapons, but they may also be cleverly exploited by tumor cells to aid in tumor progression. This multifaceted nature of B cells poses significant challenges for leveraging their potential in tumor immunotherapy. The multifaceted nature of B cells in tumor immunity presents both opportunities and challenges for their therapeutic application. By addressing the key issues outlined in this review and pursuing the proposed future research directions, we unlock the full potential of B cells in the fight against cancer.

In recent years, extensive research has emphasized the crucial function of B cells and TLS in anti-tumor immunity, providing new strategies and ideas for tumor immunotherapy. From the current perspective, the most intractable challenge in the tumor field is the inability to eradicate tumor cells that express self-antigens. This difficulty arises because the TME has fully mobilized a series of immune tolerance mechanisms, preventing specific B lymphocytes that recognize TAAs from breaking through immune tolerance and producing human IgG antibodies that recognize TAAs. It should be noted that TAAs are self-antigens, rather than the neoantigens commonly mentioned in the field of tumor immunology. Therefore, the essence of addressing this biological challenge lies in elucidating how self-reactive B lymphocytes in tumors can lower their activation threshold to break immune tolerance and produce antibodies that recognize tumor-associated self-antigens.

Currently, B cells face significant challenges and difficulties in cancer immunotherapy. First, tumor cells evade recognition by B cells by downregulating or losing the expression of TAAs. Tumor cells also secrete immune-suppressive factors to inhibit the activation and function of B cells. Moreover, the TME contains suppressive cells and cytokines that inhibit the proliferation and effector functions of B cells. Importantly, B cells themselves also have inherent limitations. In certain contexts, B cells may even play a suppressive role, inhibiting T cell-mediated anti-tumor immune responses. Chronic inflammation induced by tumors also leads to B cell functional abnormalities, such as a reduced antibody affinity. Additionally, although the antibodies produced by B cells mediate ADCC, this mechanism may have limited efficacy against solid tumors that are difficult to penetrate.

Here, we address the critical issues that require attention and outline future directions for advancing B cell-based cancer research. (i) Accurately identification of functional B cell subsets involves delineating the molecular markers that distinguish pro-tumor and anti-tumor B cell subpopulations during differentiation and activation. (ii) Elucidation of the regulatory mechanisms governing B cell functions includes unraveling the signaling pathways that promote antigen presentation and antibody secretion by B cells, as well as revealing the regulatory mechanisms underlying the production of immunosuppressive factors, such as IL-10, by suppressive B cells. (iii) Develop B cell-targeted immunotherapies, such as vaccines and mAbs, to enhance the tumor-recognizing and tumor-killing abilities of B cells for anti-tumor immunity. Investigate methods to modulate B cell signaling pathways to promote their antigen-presenting and antibody-secreting functions selectively. (iv) Create strategies to inhibit harmful B cell subsets that facilitate tumor growth. Design targeted therapies, including mAbs, to block the production of immunosuppressive factors by suppressive B cell subsets. (v) Additionally, developing precision-based approaches to decipher the complex mechanisms underlying the multifaceted function of B cells in tumor immunity and harness their beneficial functions while mitigating their tumor-promoting potential will be critical for advancing B cell-based cancer immunotherapy.

In summary, B cells face multifaceted challenges in cancer immunotherapy, arising from the tumor cells themselves, the TME, and the intrinsic limitations of B cell functions. Overcoming these barriers and harnessing the advantages of B cells is key to improving the efficacy of cancer immunotherapy.

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