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Dual role of B cells in the tumor microenvironment. B cells can have anti-tumor activities through the recognition of tumor-specific antigens and antibody production, antigen presenting cell (APC) function or direct killing of cancer cells. They can also be associated to pro-tumorigenic activities, through activation of myeloid-derived suppression cells (MDSC), production of protumorigenic cytokines and activation of immunosuppressive regulatory T cells. The pro-tumoral activity is mainly mediated by regulatory B cells. DC = dendritic cells; CTL = cytotoxic T cells; Th1 = type 1 T helper cell; APC = antigen presenting cell; CIC: circulating immune complex.
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Tumor-infiltrating lymphocytes are known to be critical in controlling tumor progression. While the role of T lymphocytes has been extensively studied, the function of B cells in this context is still ill-defined. In this review, we propose to explore the role of B cells in tumor immunity. First of all we define their dual role in promoting and inh...
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Citations
... Beyond any doubt, their involvement in adaptive immunity as antibody-secreting cells (ASCs), antigen-presenting cells (APCs), and cytotoxic cells is well clarified [37,39]. In a tumor microenvironment, B cells can be activated by cancer antigens, neoantigens, or self-antigens through T-dependent or T-independent response [40,41]. This activation can lead to the differentiation of B cells into short-lived plasmablasts, long-lived plasma cells, and memory cells, which all produce high-affinity antibodies that mediate opsonization, antibody-dependent cellular cytotoxicity (ADCC), and activation of the complement-dependent cytotoxicity (CDC), thus making B cells the pivotal effector cell of humoral immunity [37,41,42]. ...
... In a tumor microenvironment, B cells can be activated by cancer antigens, neoantigens, or self-antigens through T-dependent or T-independent response [40,41]. This activation can lead to the differentiation of B cells into short-lived plasmablasts, long-lived plasma cells, and memory cells, which all produce high-affinity antibodies that mediate opsonization, antibody-dependent cellular cytotoxicity (ADCC), and activation of the complement-dependent cytotoxicity (CDC), thus making B cells the pivotal effector cell of humoral immunity [37,41,42]. Moreover, B cells can act as APCs to activate T effector cells in TME [37,39], though the role of regulatory B cells (Bregs) in cancer immunity and their intervention in tumor growth is under great investigation. ...
... These cells can arise with many different phenotypes from different subpopulations of B cells, while the CD19 + CD24hiCD38hi phenotype seems to be the most common human one for Bregs. Their signature characteristic is the production of cytokines such as IL-10, IL-35, and TGF-β and the capacity to inhibit T cell-mediated tumor cytotoxicity [37,39,[41][42][43][44]. Furthermore, activated B cells and Bregs that express in their surface the PD-L1, an immune checkpoint, can, as mentioned before, induce tolerance and limit effector T cell responses [37,[40][41][42][43]. Finally, it is necessary to mention that the ageassociated B cells (ABCs), a unique memory B cell subpopulation, are implicated in aging, autoimmunity, and chronic inflammation through autoantibody production, cytokine induction, and T cell helper activation [45,46], yet their role in cancer and immunotherapy is understudied. ...
Globally, the efforts to find the best cancer treatment are demanding and very intensive. Immunotherapy has gained an important role as a second or sometimes first line of treatment for various types of cancer. PD-1/PD-L1 checkpoint inhibitors are an impending category of immunotherapy, and their mechanism, as well as their interaction with T cells, are well studied. However, our knowledge about any possible effect(s) of immunotherapy on B cells is limited. In this prospective study, we asked the question of any possible alterations of circulating B cells (numbers and subsets) occurring during immunotherapy in patients with cancer and of the potential correlation of such changes with the outcomes and with development of immune-related adverse events (irAEs). We enrolled 20 cancer patients who received PD-1 checkpoint inhibitors and 8 healthy donors (HD). Patients underwent regular clinical assessment and imaging using the iRECIST criteria for 6 months following immunotherapy. Peripheral blood samples were collected before and during PD-1 checkpoint inhibitor therapy, and flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) was performed, evaluating various circulating B cell subset phenotypes, including mature naïve B cells, memory B cells, regulatory B cells (Bregs), antibody-secreting cells (ASCs), and age-related B cells (ABCs). Statistical analysis was employed to compare the differences of B cells between different groups and among sequential data within the same group. Total circulating CD19+ B cell counts remained stable across both groups (responders (R), nonresponders (NR)) and timepoints. However, there was a significant rise in mature naïve B cells and decline in memory B cells at the initiation of the treatment in the R group compared to healthy donors and to the NR group. Such changes were correlated with a good response to immunotherapy. On the contrary, higher numbers of ABCs at baseline were seen in the NR group and were correlated with resistance to treatment. As far as immune-related adverse events are concerned, no significant changes were recorded among the different B cell subpopulations evaluated in both groups. Our study provides preliminary data suggesting that B cell subset changes during immunotherapy may correlate with immune checkpoint inhibitor-induced clinical responses in patients with neoplasia. Further investigations to delineate the potential role(s) of B cells in patients undergoing immunotherapy are needed.
... B cells are cyan-circled in Fig. 3b. B cells are generally believed to have anti-tumor activity by producing tumor-reactive antibodies and forming tertiary lymphoid structures [29,33]. This means that B cells are likely to be negatively associated with cancer. ...
Numerous algorithms have been proposed to identify cell types in single-cell RNA sequencing data, yet a fundamental problem remains: determining associations between cells and phenotypes such as cancer. We develop SCIPAC, the first algorithm that quantitatively estimates the association between each cell in single-cell data and a phenotype. SCIPAC also provides a p-value for each association and applies to data with virtually any type of phenotype. We demonstrate SCIPAC’s accuracy in simulated data. On four real cancerous or noncancerous datasets, insights from SCIPAC help interpret the data and generate new hypotheses. SCIPAC requires minimum tuning and is computationally very fast.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13059-024-03263-1.
... The microenvironment of the tumor has a lower number of infiltrating B cells compared to T cells. Nevertheless, recent studies indicate that the existence and function of B cells may be linked to the onset of carcinogenesis [8]. The presence of B cells in the tumor tissues of renal cell carcinoma, prostate and bladder cancer was associated with a poor prognosis [9][10][11]. ...
Background
Breast cancer is the most common cancer in females. The immune system has a crucial role in the fight against cancer. B and T cells, the two main components of the adaptive immunity, are critical players that specifically target tumor cells. However, B cells, in contrast to T cells, and their role in cancer inhibition or progression is less investigated. Accordingly, in this study, we assessed and compared the frequency of naïve and different subsets of memory B cells in the peripheral blood of patients with breast cancer and healthy women.
Results
We found no significant differences in the frequencies of peripheral CD19⁺ B cells between the patients and controls. However, there was a significant decrease in the frequency of CD19⁺IgM⁺ B cells in patients compared to the control group (P=0.030). Moreover, the patients exhibited higher percentages of atypical memory B cells (CD19⁺CD27‒IgM‒, P=0.006) and a non-significant increasing trend in switched memory B cells (CD19⁺CD27⁺IgM‒, P=0.074). Further analysis revealed a higher frequency of atypical memory B cells (aMBCs) in the peripheral blood of patients without lymph node involvement as well as those with a tumor size greater than 2cm or with estrogen receptor (ER) negative/progesterone receptor (PR) negative tumors, compared with controls (P=0.030, P=0.040, P=0.031 and P=0.054, respectively).
Conclusion
Atypical memory B cells (CD19⁺CD27‒IgM‒) showed a significant increase in the peripheral blood of patients with breast cancer compared to the control group. This increase seems to be associated with tumor characteristics. Nevertheless, additional research is necessary to determine the precise role of these cells during breast cancer progression
... The role of T lymphocytes in cancer has been widely studied, while the function of B cells in this context is still unclear [10]. However, malignant cells can escape the immune response and create a complex balance in which different immune subtypes may drive tumor progression, metastasis, and resistance to therapy [5,11]. ...
... In the light of previous studies, CD20 B cells can be found close to T cells in several types of cancer. Activated B cells act as APCs and increase T cell functionality (Th1 cells) [10,39] and affect the prognostic significance of CD3 TILs [13]. In this study, MECs and PAs have close T and B cell associations in the peripheral areas; however, they had different distributions. ...
Tumor-infiltrating lymphocytes (TILs) represent a subset of immunological constituents within the tumor microenvironment that can influence cancer growth. We retrospectively evaluate the density and pattern of CD3 and CD20 expression in salivary gland tumors and their relation to clinical pathologic parameters. A total of 44 formalin-fixed paraffin-embedded blocks of salivary gland tumors were included. These tumors were stained immunohistochemically with CD3 and CD20. The chi-square test was used to relate immune scoring, intensity, and clinical pathological parameters to different salivary tumors. p-value < 0.05 was considered statistically significant. The intra-tumoral CD3 infiltrating count was high and diffused in (71.4%) of pleomorphic adenomas (PAs) followed by mucoepidermoid carcinomas (MECs) (66.7%). At the same time, adenoid cystic carcinomas (AdCCs) exhibited significantly low infiltration (71.4%) (p = 0.046). The three types of tumors exhibited high tumor-infiltrating counts diffused in peripheral areas with significant differences between malignant tumors (p = 0.047). The intra-tumoral CD20 infiltrating count significantly differed among the tumors (p = 0.002); it was low in all PAs and AdCCs, while MECs showed an equal percentage of expression. However, in the peripheral area, PAs and MECs exhibited significantly (p = 0.007) high infiltrating counts (69.2% and 84.6), and the lowest infiltrating count was predominantly found for AdCCs. The two markers had a significant positive correlation between the mean of CD3 in the intra-tumoral and peripheral regions and CD20 in the peripheral zone across the total samples. In conclusion, the density of CD3 expression is notably higher than CD20 across tumor types. PAs and MECs showed high-density scores, while AdCCs were characterized by low scores. TIL expression was found to be significantly associated with patients’ outcomes in the intra-tumoral area.
... Here, their potential for long-term secretion of antibodies and memory cell formation sets out to be very promising for the treatment of autoimmune diseases or cancer as well as the prevention or treatment of infectious diseases [26][27][28]. In the tumor microenvironment, B cells also have the capacity to stimulate other immune cells, through secretion of cytokines, promotion of Type 1 T helper (Th1) cells and activation of cytotoxic T cells [29,30]. ...
Allogeneic cell therapies, such as those involving macrophages or Natural Killer (NK) cells, are of increasing interest for cancer immunotherapy. However, the current techniques for genetically modifying these cell types using lenti- or gamma-retroviral vectors present challenges, such as required cell pre-activation and inefficiency in transduction, which hinder the assessment of preclinical efficacy and clinical translation. In our study, we describe a novel lentiviral pseudotype based on the Koala Retrovirus (KoRV) envelope protein, which we identified based on homology to existing pseudotypes used in cell therapy. Unlike other pseudotyped viral vectors, this KoRV-based envelope demonstrates remarkable efficiency in transducing freshly isolated primary human NK cells directly from blood, as well as freshly obtained monocytes, which were differentiated to M1 macrophages as well as B cells from multiple donors, achieving up to 80% reporter gene expression within three days post-transduction. Importantly, KoRV-based transduction does not compromise the expression of crucial immune cell receptors, nor does it impair immune cell functionality, including NK cell viability, proliferation, cytotoxicity as well as phagocytosis of differentiated macrophages. Preserving immune cell functionality is pivotal for the success of cell-based therapeutics in treating various malignancies. By achieving high transduction rates of freshly isolated immune cells before expansion, our approach enables a streamlined and cost-effective automated production of off-the-shelf cell therapeutics, requiring fewer viral particles and less manufacturing steps. This breakthrough holds the potential to significantly reduce the time and resources required for producing e.g. NK cell therapeutics, expediting their availability to patients in need.
... B cell and IFN-related immune response pathways were found to be upregulated in CRC patients who responded to neoadjuvant chemoradiotherapy (nCRT) [17]. B cells not only generate antibodies and secrete cytokines, but also regulate T cells and affect the innate immune response [18]. Damage-associated molecular patterns are released and tumor antigens are exposed to activate antitumor response when tumor cells are treated by nCRT [19]. ...
This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.
... Our study ndings indicate a positive correlation between M0 and M2 macrophage in ltration and risk scores. T cells, B cells, and NK cells are immune cells with anti-tumor properties, and the augmentation of mitochondrial lysosome activity serves to bolster their anti-tumor e cacy(38) (39,40). Our study revealed diminished in ltration of these cells in high-risk patients. ...
Background
The impact of mitochondrial and lysosomal co-dysfunction on breast cancer patient outcomes is unclear. The objective of this study is to develop a predictive machine learning (ML) model utilizing mitochondrial and lysosomal co-regulators in order to enhance the prognosis for individuals with BC.
Methods
Differences and correlations of mitochondrial and lysosome related genes were screened and validated. WGCNA and univariate Cox regression were employed to identify prognostic mitochondrial and lysosomal co-regulators. ML was utilized to further selected these regulators as mitochondrial and lysosome-related model signature genes (mlMSGs)and constructed models. The association between the immune and mlMSGs score was investigated through scRNA-seq. Finally, the expression and function of the key gene SHMT2 were confirmed through in vitro experiments.
Results
According to the C-index, the coxboost+ Survivor-SVM model was identified as the most suitable for predicting outcomes in BC patients. Subsequently, patients were stratified into high and low risk groups based on the model, which demonstrated strong prognostic accuracy. While the overall immunoinfiltration of immune cells was decreased in the high-risk group, it was specifically noted that B cell mlMSGs activity remained diminished in high-risk patients. Additionally, the study found that SHMT2 promoted the proliferation, migration, and invasion of BC cells.
Conclusion
This study shows that the ML model accurately predicts the prognosis of BC patients. Analysis conducted through the model has identified decreased B-cell immune infiltration and reduced mlMSGs activity as significant factors influencing patient prognosis. These results may offer novel approaches for early intervention and prognostic forecasting in BC.
... B cells promote tumour progression by promoting angiogenesis, generating pro-inflammatory responses, and directly or indirectly inhibiting T cell activation [71][72][73]. However, B cells also play a dual role in tumour immunity [74], with their known anti-tumour activity, the ability to directly kill tumour cells, functionality as antigen-presenting cells, and ability to recognize antigens and facilitate the production of specific antibodies. Wu et al. [75] showed that B cells promote the formation of MPE in vivo by regulating CD4 + T cells. ...
Immune microenvironment and immunotherapy have become the focus and frontier of tumor research, and the immune checkpoint inhibitors has provided novel strategies for tumor treatment. Malignant pleural effusion (MPE) is a common end-stage manifestation of lung cancer, malignant pleural mesothelioma and other thoracic malignancies, which is invasive and often accompanied by poor prognosis, affecting the quality of life of affected patients. Currently, clinical therapy for MPE is limited to pleural puncture, pleural fixation, catheter drainage, and other palliative therapies. Immunization is a new direction for rehabilitation and treatment of MPE. The effusion caused by cancer cells establishes its own immune microenvironment during its formation. Immune cells, cytokines, signal pathways of microenvironment affect the MPE progress and prognosis of patients. The interaction between them have been proved. The relevant studies were obtained through a systematic search of PubMed database according to keywords search method. Then through screening and sorting and reading full-text, 300 literatures were screened out. Exclude irrelevant and poor quality articles, 238 literatures were cited in the references. In this study, the mechanism of immune microenvironment affecting malignant pleural effusion was discussed from the perspectives of adaptive immune cells, innate immune cells, cytokines and molecular targets. Meanwhile, this study focused on the clinical value of microenvironmental components in the immunotherapy and prognosis of malignant pleural effusion.
... In addition, B cells have been revealed to enormously impact molding cancer immune response and are closely related to prognosis of patients 23 . A total of 7347 B cells were analyzed, and three subtypes were identified: follicular B cells, germinal center B cells and plasma B cells (Fig. 2a). ...
Metabolic reprogramming has been observed in cancer metastasis, whereas metabolic changes required for malignant cells during lymph node metastasis of esophageal squamous cell carcinoma (ESCC) are still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) of paired ESCC tumor tissues and lymph nodes to uncover the reprogramming of tumor microenvironment (TME) and metabolic pathways. By integrating analyses of scRNA-seq data with metabolomics of ESCC tumor tissues and plasma samples, we found nicotinate and nicotinamide metabolism pathway was dysregulated in ESCC patients with lymph node metastasis (LN ⁺ ), exhibiting as significantly increased 1-methylnicotinamide (MNA) in both tumors and plasma. Further data indicated high expression of N-methyltransferase (NNMT), which converts active methyl groups from the universal methyl donor, S-adenosylmethionine (SAM), to stable MNA, contributed to the increased MNA in LN ⁺ ESCC. NNMT promotes epithelial–mesenchymal transition (EMT) and metastasis of ESCC in vitro and in vivo by inhibiting E-cadherin expression. Mechanically, high NNMT expression consumed too much active methyl group and decreased H3K4me3 modification at E-cadherin promoter and inhibited m6A modification of E-cadherin mRNA, therefore inhibiting E-cadherin expression at both transcriptional and post-transcriptional level. Finally, a detection method of lymph node metastasis was build based on the dysregulated metabolites, which showed good performance among ESCC patients. For lymph node metastasis of ESCC, this work supports NNMT is a master regulator of the cross-talk between cellular metabolism and epigenetic modifications, which may be a therapeutic target.
... B cells play a crucial role in tumor immunity, with their protumor or antitumor effects depending on the tumor microenvironment (151). PARP can affect B cell homeostasis. ...
Polyadenosine diphosphate-ribose polymerase (PARP) is a key modifying enzyme in cells, which participates in single-strand break repair and indirectly affects double-strand break repair. PARP inhibitors have shown great potential in oncotherapy by exploiting DNA damage repair pathways, and several small molecule PARP inhibitors have been approved by the U.S. Food and Drug Administration for treating various tumor types. PARP inhibitors not only have significant antitumor effects but also have some synergistic effects when combined with radiotherapy; therefore they have potential as radiation sensitizers. Here, we reviewed the advances and implications of PARP inhibitors in tumor radiotherapy sensitization. First, we summarized the multiple functions of PARP and the mechanisms by which its inhibitors exert antitumor effects. Next, we discuss the immunomodulatory effects of PARP and its inhibitors in tumors. Then, we described the theoretical basis of using PARP inhibitors in combination with radiotherapy and outlined their importance in oncological radiotherapy. Finally, we reviewed the current challenges in this field and elaborated on the future applications of PARP inhibitors as radiation sensitizers. A comprehensive understanding of the mechanism, optimal dosing, long-term safety, and identification of responsive biomarkers remain key challenges to integrating PARP inhibition into the radiotherapy management of cancer patients. Therefore, extensive research in these areas would facilitate the development of precision radiotherapy using PARP inhibitors to improve patient outcomes.
