Jikai He, Jiaqi Jia, Wenhao Qu, Lizhou Jia, Wei Zhao. The function and regulatory mechanism of B cells in tumor immunity[J]. Blood&Genomics, 2022, 6(2): 103-113. DOI: 10.46701/BG.2022022022031
Citation:
Jikai He, Jiaqi Jia, Wenhao Qu, Lizhou Jia, Wei Zhao. The function and regulatory mechanism of B cells in tumor immunity[J]. Blood&Genomics, 2022, 6(2): 103-113. DOI: 10.46701/BG.2022022022031
Jikai He, Jiaqi Jia, Wenhao Qu, Lizhou Jia, Wei Zhao. The function and regulatory mechanism of B cells in tumor immunity[J]. Blood&Genomics, 2022, 6(2): 103-113. DOI: 10.46701/BG.2022022022031
Citation:
Jikai He, Jiaqi Jia, Wenhao Qu, Lizhou Jia, Wei Zhao. The function and regulatory mechanism of B cells in tumor immunity[J]. Blood&Genomics, 2022, 6(2): 103-113. DOI: 10.46701/BG.2022022022031
Research Center for Prevention and Treatment of Drug Resistant Microbial Infection, Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China
2.
Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
B cells are important components of the human immune system, and play a role in the process of specific immunity. In recent years, research on B cells and tumor immunity has made rapid progress. Studies have shown that different types of B cells play different roles in the tumor microenvironment (TME) through a variety of mechanisms. Tumor-infiltrating B cells (TIBs) in the TME play an anti-tumor role by secreting antibodies and presenting antigens, while regulatory B cells (Bregs) inhibit the immune response by secreting a variety of cytokines, thereby promoting tumor immune escape. This review introduces the roles and mechanisms of different subtypes of B cells in different types of tumors.
The tumor microenvironment (TME) is a special and complex biological environment that affects the growth, invasion, and metastasis of tumor cells. There are several types of immune cells in the TME, including T cells, B cells, macrophages, natural killer (NK) cells, adipocytes, fibroblasts, etc[1]. In the TME, B cells play different immunoregulatory roles according to their different locations and subtypes. When B cells are stimulated by antigens, they differentiate into plasma cells, produce and secrete immunoglobulin antibodies, and participate in humoral immunity[2]. B cells can also act as antigen presenting cells (APCs) by presenting low concentrations of antigen to T cells, and activating T cells to play an anti-tumor role[3]. In addition, regulatory B cells (Bregs), newly discovered in recent years, can inhibit the immune response by secreting some negative regulators, including interleukin-10 (IL-10), interleukin-35 (IL-35), and transforming growth factor-β (TGF-β), thereby playing a pro-tumor role[4] (Fig. 1). In the following paper, we introduce the different roles and mechanisms of B cells in tumor immunity.
Figure
1.
The roles and mechanisms of different types of B cells in the TME.
TME: tumor microenvironment; TIBs: tumor-infiltrating B cells; ADCC: antibody-dependent cell-mediated cytotoxicity; CDC: complement dependent cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; MHC: major histocompatibility complex; TCR: T cell receptor; Tregs: regulatory T cells; Bregs: regulatory B cells; NK cells: natural killer cells; Th17: T helper cell 17; Th1: T helper cell 1; DC: dendritic cell; IL-10: interleukin-10; IL-35: interleukin-35; TGF-β: transforming growth factor-β.
THE ROLES AND MECHANISMS OF DIFFERENT TYPES OF B CELLS IN THE TME
In the past decade, the roles of T cells in tumor immunity were widely studied, while little is known about the roles of B cells. At present, some studies have shown that the existence and functions of B cells in the TME may be related to the prognosis of cancer, and different subtypes of B cells play different roles in the TME[5–8].
Tumor infiltrating B cells (TIBs)
The TME is a special and complex biological environment that affects the growth, invasion, and metastasis of tumor cells[9]. In addition to stromal cells, fibroblasts, and endothelial cells, the TME also contains innate immune cells (macrophages, neutrophils, dendritic cells, innate lymphoid cells, myeloid suppressor cells, NK cells, etc.) and adaptive immune cells (T cells and TIBs)[10]. T cells, NK cells, dendritic cells (DCs), macrophages, and other cells in the TME have been extensively studied. However, the role of TIBs in the TME is still not entirely clear.
High endothelial venules (HEVs) in the TME, which recruit endothelial cells, tumor cells, and T cells, can recruit B cells to migrate into the TME through the expression of chemokine ligand 13 (CXCL13), and play an anti-/pro-tumor immunity role[11]. TIBs may play different immune roles in the TME according to their different locations and subtypes. TIBs not only achieve tumor antigen presentation through the B cell surface receptor (BCR)[12], but also regulate the biological activity of T cells by secreting a variety of cytokines, so as to change the killing effect of T cells in the anti-tumor process[13]. At the same time, TIBs can maintain the structure and function of tertiary lymphoid structures (TLSs) by secreting tumor-specific antibodies, and play an anti-tumor role[14]. In addition, several reports indicated that TIBs can secrete IL-10/IL-35/TGF-β cytokines, thereby promoting the development of tumors[15]. TIBs were also found in a variety of solid tumors such as breast cancer, cervical cancer, ovarian cancer, and non-small cell lung cancer (NSCLC), and TIBs with higher density were often associated with a better prognosis[16].
Plasma cells
Plasma cells are formed by the differentiation and proliferation of B cells under the stimulation of antigens and no longer have the ability of differentiation and proliferation. Our previous study confirmed that the mature tertiary lymphoid structures in gastric cancer tissues had germinal center (GC)-like structures[17]. In the GC of TLSs, follicular dendritic cells (FDCs) can present antigens to B cells for recognition, and then the B cells are activated with the help of T follicular helper (Tfh) cells, and go on to proliferate and differentiate into plasma cells[8]. Plasma cells produce a large number of high-affinity antibodies including immunoglobulin A (IgA) and immunoglobulin G (IgG), thereby exerting an anti-tumor humoral immune response[18–19]. Antibodies produced by plasma cells can participate in anti-tumor immunity through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP)[2,20–21]. In addition, tumor specific antigens in the TME can activate B cells to differentiate into plasma cells which further produce tumor antigen specific antibodies. The production of tumor specific antibodies can promote the regulation and phagocytosis of tumor cells by macrophages and DCs, and induce tumor cell lysis by CDC and ADCC[22–23].
Antigen-presenting B cells
Although DCs are known as masters of antigen presentation, they are often hampered by tumor modification[15]. Therefore, the ability of B cells to present tumor specific antigens to T cells may play a crucial role in promoting anti-tumor immunity. B cells can uptake and process treated antigens, load the treated antigen peptides on major histocompatibility complex (MHC)-Ⅰ/MHC-Ⅱ molecules, and present them to CD8+/CD4+ T cells[24]. Meanwhile, tumor-associated antigens activate specific B cells which differentiate into plasma cells, and produce IgG antibodies. Tumor-associated antigens form immune complexes with their corresponding IgG, which are subsequently captured by B cells and transferred to FDCs[25].
Bregs
As a newly discovered functional subgroup of B cells in recent years, Bregs play an important role in tumor immune escape by secreting negative regulatory factors such as IL-10, IL-35, and TGF-β to inhibit the immune response of the body[26–27].
Bregs can inhibit T-helper (Th) 1/Th17 cell differentiation by producing IL-10, thus helping tumors evade the body's immune attack[28]. In addition, Bregs can induce the generation of T regulatory cells (Tregs) through the production of IL-10, thereby inhibiting the activity of cytotoxic T lymphocytes and promoting tumor immune escape [29–30].
Bregs mediate immunosuppression by the production of IL-35, which inhibits the function of NK cells, T cells, and macrophages[31]. It can also act by inhibiting the differentiation of Th1/Th17 cells and inducing the production of Tregs[32]. IL-35 not only promotes tumor growth and metastasis by transforming resting B and T cells into Bregs and Tregs that can secrete IL-10 and IL-35[33–34], but also enhances the activity of Bregs by activating signaling molecules such as signal transducer and activator of transcription 1 (STAT1), and signal transducer and activator of transcription 3 (STAT3)[35].
Bregs also secrete TGF-β, which has a dual role. In the early stage of tumorigenesis, TGF-β+ Bregs inhibit tumor growth by inhibiting the cycle procession of tumor cells and promoting their apoptosis, while in the late stage of tumors, TGF-β+ Bregs promote tumor growth[36]. The main mechanisms of TGF-β in promoting tumor growth include inhibiting the activity of NK cells, inhibiting the proliferation of DCs, and the expression of major histocompatibility complexes[37].
INFILTRATION OF B CELLS IN DIFFERENT TUMORS AND ROLES
B cell subtypes differ greatly in the micro-environment of different tumors, so tumor immune surveillance and immune responses also vary greatly, which also leads to different immunotherapy results for different types of tumors.
Lung cancer
The research of Cui Can et al. showed that the enrichment of CD4+ T cells and GC B cells was correlated with favorable clinical outcomes in patients with lung adenocarcinoma (LUAD)[38]. Moreover, this study showed that LUAD tumor cells expressed new antigens recognized by B cells and T cells. Tumor neoantigens can regulate the fate of tumor-specific CD4+ T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8+ T cell effector functions[38]. TIBs showed to be cytotoxic to lung cancer cells by secreting granzyme B and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Fig. 2)[14]. In addition, B cells also contribute to the immune response of infiltrating T cells in tumor tissues. Recent studies suggest that the high density of B cells in TLSs of NSCLC is associated with increased CD4+ T cell receptor clonality[39]. In addition, NSCLC patients with higher levels of CD8+/CD4+ T cells and CD20high B cell infiltration had better overall survival[40]. These studies indicate that TIBs can promote T cell-mediated antitumor immunity (Fig. 2). Moreover, a high frequency of CD19+IL-10+ Bregs was found in patients with advanced lung cancer[33], which can recruit Tregs and myeloid-derived suppressor cells (MDSC) in the peripheral circulation by secreting large amounts of IL-10[41]. However, it is unclear whether Bregs can directly or indirectly affect the progression of lung cancer.
Figure
2.
The dynamic conversion processes and immunomodulatory effects of B cells in cancer.
HEV: high endothelial venule; TLS: tertiary lymphoid structure; TME: tumor microenvironment; TIBs: tumor-infiltrating B cells; ADCC: antibody-dependent cell-mediated cytotoxicity; CDC: complement dependent cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; MHC: major histocompatibility complex; TCR: T cell receptor; Tregs: regulatory T cells; Bregs: regulatory B cells; NK cells: natural killer cells; Th17: T helper cell 17; Th1: T helper cell 1; GC: germinal center; IL-10: interleukin-10; IL-35: interleukin-35; TGF-β: transforming growth factor-β; TRAIL: tumor necrosis factor (TNF)-related apoptosis-inducing ligand; BTK: Bruton's tyrosine kinase; IgA: immunoglobulin A.
Studies showed that the density of TIBs in untreated primary breast cancer patients increased compared with that of normal breast tissue[42]. Multiplex ion beam imaging revealed persistent depletion of TIBs along the tumor boundary of triple-negative breast cancer (TNBC), however, reasons for this relative reduction were unclear[43]. TNBC with high plasma cell density was significantly positively correlated with the expression of IgG Kappa+CD38+ cells, CD20+ B cells, and TLSs, and TNBC patients with high plasma cell density had better prognoses[44]. In addition, studies showed that high expression of programmed cell death-ligand 1 (PD-L1) in invasive breast cancer tumor (IBCa) cells can induce CD19+ B cells to differentiate into CD19+CD24+CD38+ B cells, which secrete IL-10 in IBCa TME. One study also found that CD19+ B cells in tumor tissues of IBCa patients could induce CD4+ T cells to differentiate into CD4+CD25+Foxp3+ Tregs, thereby inhibiting anti-tumor immunity. These results indicate that different types of B lymphocytes in breast cancer may play different immunomodulatory roles[45].
Pancreatic cancer
Studies showed that immunoglobulins produced by spleen B cells in patients with pancreatic cancer can form immune complexes, which can induce tumor-associated macrophages (TAMs) to differentiate into M2 macrophages, and play a role in inhibiting CD8+ T cells, thereby promoting the growth of pancreatic cancer tumors[46]. It has also been reported that B cells can induce the polarization of M2 phenotype of macrophages in pancreatic cancer by activating Bruton's tyrosine kinase (BTK) signaling pathway (Fig. 2)[47]. On the other hand, fibroblasts in pancreatic cancer tumor tissues can recruit Bregs by secreting CXCL13 to promote tumor growth. However, these immunosuppressive B cells only account for 10% of the total B cell population in pancreatic cancer[48]. In addition, several studies showed that the administration of five different interferon gene-stimulating factor (STING) agonists, including cyclic GMP-AMP (cGAMP), promoted the elevation of interleukin-35, which induced the "transformation" of Bregs into a new Breg subpopulation in pancreatic cancer patients. Their study also showed that the STING-IL-35 axis in B cells inhibited the proliferation of NK cells and attenuated the NK-driven antitumor response (Fig. 2)[49]. In pancreatic cancer, high B-cell infiltration was associated with a better prognosis, especially when B cells gathered in TLSs[50].
Colorectal cancer (CRC)
Studies showed that the presence of a large number of infiltrating CD20+ B cells in colorectal cancer (CRC) tissues was beneficial to the prognosis of patients, and CD20+ B cells in lung/liver metastases tissues from CRC were also conducive to the prognosis of patients[51–52]. In addition, the high expression of CD138+ B cells in tumor tissues was also associated with a better prognosis[53]. Another study revealed that the density of TIBs was higher in the right CRC and early CRC tissues[54]. In our previous study, we also found that signal sequence receptor protein 4 (SSR4) was significantly expressed in the cytoplasm of plasma cells, and advanced CRC patients with SSR4high plasma cells had a better prognosis[55].
Ovarian cancer
A large number of studies showed that ovarian cancer patients with high B-cell infiltration had a better prognosis, while compared with those with CD8+ TILs alone, ovarian cancer patients with CD20+ and CD8+ TILs had a better prognosis[56–57]. These results indicate that the cooperative interaction between these lymphocyte subsets leads to stronger anti-tumor immunity[58]. Biswas et al. found that B cells in patients with high-grade serous ovarian cancer (HGSOC) mainly produced IgA, which bound to polymeric IA receptor (PIGR) on ovarian cancer cells. In addition, IgA transcytosis induces transcriptional changes of inflammatory pathways in tumor cells. Further research showed that IgA made tumor cells sensitive to cytotoxic T lymphocyte (CTL)-mediated cytotoxicity in an Fc/PIGR dependent manner in vitro and in vivo, which also helped to hinder the occurrence and development of malignancy. Therefore, IgA can inhibit the growth of ovarian cancer by coordinating the interaction among tumor cells, T cells, and B cells. These studies suggest that IgA combined with immunotherapy may be used as a strategy for combination therapy in ovarian cancer[57,59]. However, several studies showed that patients with increased expression of CD138+/CD19+ B cells in epithelial ovarian cancer (EOC) had a poor prognosis, which may be due to different subtypes and small sample size[60–61].
Gastric cancer
Our previous research revealed that compared with peripheral blood, a large number of mucosal associated lymphoid tissue B cells (MALT-B) were detected in gastric adenocarcinoma tissues. We found that these MALT-B cells played an anti-tumor role by secreting IgA and mediating humoral immunity[17]. In addition, IgA polymers can activate complement bypass pathway to play an important role in gastric adenocarcinoma TME[17]. There were a large number of CD20+ B cells infiltrated in gastric cancer, and the level of CD20+ B cell infiltration was positively correlated with T cell infiltration level. Moreover, high level of tumor infiltration (CD20+ B cells) was associated with low lymph node metastasis, low TNM staging, and could prolong the overall survival (OS) and disease-free survival (DFS) of gastric cancer patients[62]. Literature studies showed that the proportion of CD19+CD24hiCD38hi Bregs in the peripheral blood of patients with gastric cancer increased significantly. Bregs can inhibit the production of interferon (IFN)-γ and TNF-α by CD4+ Th cells through secreting IL-10 and TGF-β1, and induce the differentiation of CD4+FoxP3+ Tregs through secreting TGF-β1. Therefore, Bregs is associated with a poorer prognosis in patients with gastric cancer[63].
Hepatocellular carcinoma (HCC)
Garnelo et al. analyzed 112 hepatocellular carcinoma (HCC) samples and found that tumor-infiltrating T and B cells were in close contact with each other[64]. Higher T and B cell densities were correlated with better survival in HCC patients, and the density of TIBs was correlated with enhanced granzyme B and IFN-γ, and further decreased tumor cell viability. Brunner et al. retrospectively analyzed 2158 HCC samples and found that a large amount of B-cell infiltration in HCC was associated with prolonged overall survival[65]. Shao's study found that compared with the tumor region and non-tumor region of liver cancer, the percentage of CD20+ B cells at the tumor edge was higher[66]. In addition, the study showed that the percentage of Bregs in peripheral blood from liver cancer patients was significantly higher than that of healthy people[66]. Further in vivo experiments confirmed that the migration of Bregs into tumor tissues promoted the growth of HCC tumors. In vitro co-culture experiments verified that Bregs directly interacted with HCC cells through CD40/CD154 signaling pathway, which could promote the growth and invasion of HCC. Xue et al. found that the number of Bregs was negatively correlated with the number of CD4+ T cells in patients with HCC, and Bregs could inhibit the cytotoxicity of CD4+ T cells[67]. In summary, CD20+ B cells are immune cells associated with a good prognosis of HCC, while Bregs are associated with a poor prognosis, and the pro-cancer effect of Bregs may be associated with the decreased activity of other cancer-suppressive immune cells.
Melanoma
Numerous studies showed that a large number of B cells infiltrating around melanoma lesions were associated with a better prognosis[68–69]. However, the role of B cells in melanoma is controversial. TIBs were shown to contribute to anti-tumor immunity by generating antibody response to melanoma-associated antigens. Studies showed that 28% of melanoma-derived B cells were capable of binding to various antigens expressed by melanoma cell lines, compared with only 2% of B cells from healthy individuals[70]. Plasma cells in melanoma tissues mainly secreted IgG and IgA, which played an effective role in anti-tumor through ADCC (Fig. 2)[71]. However, it was also shown that melanoma cells produced fibroblast growth factor 2 (FGF-2), which stimulated B cells to produce insulin-like growth factor-1 (IGF-1), a key molecule in melanoma resistance to BRAF and MAP-ERK kinase (MEK) inhibitors[72]. In addition, it was found that Bregs inhibited Th1-type cytokine secretion by CD8+ T cells via IL-10, and further suppressed the anti-tumor immune response[73].
Esophageal squamous cell carcinoma (ESCC)
Studies showed that a high density of T and B cell subsets had synergistic beneficial prognostic effects in the TME of esophageal cancer and gastric adenocarcinoma. However, the infiltrating B cells and plasma cells in esophageal squamous cell carcinoma (ESCC) tissue were much higher than the activated T cells[74]. One study showed that IgG2-plasma cells constituted the major form of B-cell-mediated anti-tumor immunity in ESCC[75]. In addition, Lin Lu et al. showed that interleukin-17A (IL-17A) could promote B cell migration in ESCC by stimulating tumor cells to produce more chemokines[76]. On the other hand, IL-17A can enhance the anti-tumor ability of B cells by producing more immunogenic antibodies and cytolytic molecules. However, some studies showed that ESCC patients with high expression of high mobility group box-1 (HMGB1) gene and highly infiltrated B cells had a worse prognosis, as B cells promoted angiogenesis in a HMGB1-dependent manner, thereby promoting the growth of esophageal tumors in vivo[77].
Head and neck squamous cell carcinoma (HNSCC)
Studies showed that human papillomavirus (HPV)-specific B cells were present in HPV+ HNSCC, and secreted a large amount of HPV-specific IgG antibodies, which were similar to HIV-specific antibodies and showed high somatic supermutation (SHM)[78]. It was shown that the infiltration of CD20+ B cells were increased in HNSCC and were related to prolonged DFS[79]. Flow cytometry analysis showed that the expression level of CD86+CD21− antigens presenting B cells were significantly increased in tumor tissue samples, while immunoglobulin D (IgD)−CD27+ memory B cells were increased in the tumor tissues and peripheral blood of HNSCC patients compared with healthy donors[80]. In addition, studies showed that Bregs preferentially localized within the TME and promoted immunosuppression by inhibiting the function of B effector cells in HNSCC[81–82].
Renal cell carcinoma (RCC)
The presence of TLSs in tumors is often associated with a favorable prognosis and immune response to cancer. The research undertaken by Maxime Meylan et al. showed that IgG+/IgA+ plasma cells in TLSs+ renal cell carcinoma (RCC) spread into the tumor bed along fibroblast tracks. Treatment response and progression-free survival in RCC patients treated with immunocheckpoint inhibitors were positively correlated with the expression of IgG-tumor cells[83]. And some studies showed that the density of TIBs was not only an independent prognostic factor for metastatic renal cell cancer (mRCC) patients, but also a predictive marker for tyrosine kinase inhibitor (TKI) therapy response. TIBs may potently enhance the anti-tumor effect by recruiting and activating CD8+ TILs in mRCC[84]. The presence of TLSs in tumors is often associated with a favorable prognosis.
SUMMARY AND PROSPECTS
To sum up, the role of B cells in tumor immune escape is a "double-edged sword". In most cancers, CD20 and CD138 phenotypes of B cells are associated with better prognoses, while Bregs are often associated with poor prognoses in cancer patients (Table 1). CD20+ B and plasma cells play an anti-tumor function by enhancing T cell response and ADCC, while Bregs mainly mediate tumor immune escape by secreting cytokines. The role of B cells in tumor immunity is not black or white, and different phenotypes of B cells play different roles in different locations of the tumor. However, with the further development of techniques such as single-cell sequencing and immune bank sequencing, we will have a better understanding of the different phenotypes of TIBs and their interactions with the TME, which will provide new ideas for tumor immunotherapy.
Table
1.
Prognostic impact of B cells in human cancers
Types of cancers
Number of cases
B cell phenotypes
Results
Conclusions
References
NSCLC
202
CD20
OS (HR=0.523, 95% CI 0.323–0.817, P=0.004)
High B cell levels were significantly associated with longer OS in NSCLC patients.
The results of double staining immunohistochemistry of interleukin-10 and CD19 revealed the 5-year overall survival rates of the Bregs low expression group and the Bregs high expression group were 65.4% and 13.3%, respectively.
This work was supported by the National Natural Science Foundation of China (Grant No. 82273196) and the Key Project of Nanjing Health Science and Technology (Grant No. ZKX22029). The authors thank all participants in the study.
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The results of double staining immunohistochemistry of interleukin-10 and CD19 revealed the 5-year overall survival rates of the Bregs low expression group and the Bregs high expression group were 65.4% and 13.3%, respectively.
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