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Tumor immune microenvironment is strongly associated with the malignancy behavior of hepatocellular carcinoma (HCC). However, the immune function and regulatory mechanisms of B cells in HCC remain unclear. The expression differences between B cell high‐ and low‐infiltration HCC samples are explored to identify the key regulator. Pre‐mRNA processing factor 19 (PRP19) expression is increased in B cell low‐infiltrated tissues and negatively correlated with the B cell marker, CD20. Inhibition of PRP19 expression promoted B cell infiltration in tumor tissue and impeded HCC growth. Mechanically, the co‐immunoprecipitation (Co‐IP) assay revealed that PRP19 interacts with DEAD‐box helicase 5 (DDX5), leading to ubiquitination and degradation of the DDX5 protein. The attenuated DDX5 impairs CXCL12 mRNA stability to suppress B cell recruitment and plasma cell differentiation via CXCL12/CXCR4 axis. Moreover, the adoptive transfer of CXCR4+ B cells combined with CXCL12 treatment in mice models effectively inhibits HCC development by reshaping the immune response. The expression of PRP19, DDX5, and infiltrating B cells are recognized as clinical prognosis indicators for HCC patients. Overall, this study provides valuable insights into the clinical benefits of HCC immunotherapy by targeting PRP19 and modulating tumor‐infiltrating B cell immune function. [ABSTRACT FROM AUTHOR]

Simple Summary: This study identified tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) as potential prognostic indicators in brain metastases (BMs) derived from gastrointestinal (GI) cancers. Higher densities of TIBs and TRMs in the BM tissues significantly correlated with improved overall survival after BM diagnosis. These findings suggest that quantifying TIB and TRM levels in surgically resected BM samples could provide valuable prognostic information to guide treatment decisions and follow-up strategies for patients with this lethal condition. Additionally, we revealed distinct spatial distributions and characteristics of these lymphocyte subsets, which advanced our understanding of the BM immune microenvironment. Further studies with larger cohorts are needed to validate these findings and explore their potential therapeutic implications. Background/Objectives: Tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) play significant roles in antitumor immunity. However, their prognostic relevance in brain metastases (BMs) derived from gastrointestinal (GI) cancers remains unclear. This study aimed to investigate the prognostic significance of TIBs and TRMs in GI cancer-derived BMs (GIBMs). Methods: Retrospective histopathological analyses were performed on surgically resected GIBM tissues from 13 patients. The densities of tumor-infiltrating lymphocytes (TIL) subsets (TIBs, CD4+ T cells, CD8+CD103+ TRMs, and CD8+CD103- non-TRMs) were quantified and correlated with clinical parameters and overall survival (OS) including the Graded Prognostic Assessment (GPA). Results: TIBs and CD4+ T cells were predominantly accumulated in the tumor stroma, particularly around blood vessels, where they formed lymphocyte clusters without characteristics of tertiary lymphoid structures (TLSs). In contrast, TRMs more deeply infiltrated into the tumor epithelium than their counterpart non-TRMs. Positive correlations were found between TIB density and both the prognostic prediction of GPA and overall survival (OS) after BM diagnosis or surgery. Furthermore, increased densities of TIBs and TRMs were associated with enhanced survival after BM diagnosis. Conclusions: TIB and TRM densities in BM tissues could serve as reliable prognostic indicators for survival in patients with GIBMs. This study provides crucial insights for the development of novel immunotherapeutic strategies against this lethal disease. [ABSTRACT FROM AUTHOR]

Abstract Tumor immune microenvironment is strongly associated with the malignancy behavior of hepatocellular carcinoma (HCC). However, the immune function and regulatory mechanisms of B cells in HCC remain unclear. The expression differences between B cell high‐ and low‐infiltration HCC samples are explored to identify the key regulator. Pre‐mRNA processing factor 19 (PRP19) expression is increased in B cell low‐infiltrated tissues and negatively correlated with the B cell marker, CD20. Inhibition of PRP19 expression promoted B cell infiltration in tumor tissue and impeded HCC growth. Mechanically, the co‐immunoprecipitation (Co‐IP) assay revealed that PRP19 interacts with DEAD‐box helicase 5 (DDX5), leading to ubiquitination and degradation of the DDX5 protein. The attenuated DDX5 impairs CXCL12 mRNA stability to suppress B cell recruitment and plasma cell differentiation via CXCL12/CXCR4 axis. Moreover, the adoptive transfer of CXCR4+ B cells combined with CXCL12 treatment in mice models effectively inhibits HCC development by reshaping the immune response. The expression of PRP19, DDX5, and infiltrating B cells are recognized as clinical prognosis indicators for HCC patients. Overall, this study provides valuable insights into the clinical benefits of HCC immunotherapy by targeting PRP19 and modulating tumor‐infiltrating B cell immune function.

According to the World Health Organization (WHO), gastric cancer (GC) is the fourth leading cause of tumor-related mortality globally and one of the most prevalent malignant tumors. To better understand the role of tumor-infiltrating B cells (TIBs) in GC, this work used single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing (bulk RNA-Seq) data to identify candidate hub genes. Both scRNA-Seq and bulk RNA-Seq data for stomach adenocarcinoma (STAD) were obtained from the GEO and TCGA databases, respectively. Using scRNA-seq data, the FindNeighbors and FindClusters tools were used to group the cells into distinct groups. Immune cell clusters were sought in the massive RNA-seq expression matrix using the single-sample gene set enrichment analysis (ssGSEA). The expression profiles were used in Weighted Gene Coexpression Network Analysis (WGCNA) to build TCGA's gene coexpression networks. Next, univariate Cox regression, LASSO regression, and Kaplan–Meier analyses were used to identify hub genes in scRNA-seq data from sequential B-cell analyses. Finally, we examined the correlation between the hub genes and TIBs utilizing the TISIDB database. We confirmed the immune-related markers in clinical validation samples using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). 15 cell clusters were classified in the scRNA-seq database. According to the WGCNA findings, the green module is most associated with cancer and B cells. The intersection of 12 genes in two separate datasets (scRNA and bulk) was attained for further analysis. However, survival studies revealed that increased C-X-C motif chemokine receptor 4 (CXCR4) expression was linked to worse overall survival. CXCR4 expression is correlated with active, immature, and memory B cells in STAD were identified. Finally, RT-PCR and IHC assays verified that in GC, CXCR4 is overexpressed, and its expression level correlates with TIBs. We used scRNA-Seq and bulk RNA-Seq to study STAD's cellular composition. We found that CXCR4 is highly expressed by TIBs in GC, suggesting that it may serve as a hub gene for these cells and a starting point for future research into the molecular mechanisms by which these immune cells gain access to tumors and potentially identify therapeutic targets. [ABSTRACT FROM AUTHOR]

The occurrence and development of tumors are closely associated with abnormalities in the immune system's structure and function, with tumor immunotherapy being intricately linked to the tumor microenvironment (TME). Early studies on lymphocytes within the TME primarily concentrated on T cells. However, as research has advanced, the multifaceted roles of tumor-infiltrating B cells (TIL-Bs) in tumor immunity, encompassing both anti-tumor and pro-tumor effects, have garnered increasing attention. This paper explored the composition of the TME and the biological characteristics of TIL-Bs, investigating the dual roles within the TME to offer new insights and strategies for tumor immunotherapy. [Display omitted] • Dual roles of tumor-infiltrating B cells in tumor microenvironment: anti-tumor and pro-tumor effects. • Tumor-infiltrating B cells boost anti-tumor immunity via antigen presentation, antibody production, cytokine secretion, etc. • Regulatory B cells aid tumor immune evasion by releasing suppressive cytokines, specific antibodies, and metabolites. • Insights into Tumor-infiltrating B cells may offer potential new targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is classified into core molecular subgroups (wingless activated (WNT), sonic hedgehog activated (SHH), Group 3 (G3), and Group 4 (G4)). In this study, we analyzed the tumor-infiltrating immune cells and cytokine profiles of 70 MB patients in Taiwan using transcriptome data. In parallel, immune cell composition in tumors from the SickKids cohort dataset was also analyzed to confirm the findings. The clinical cohort data showed the WNT and G4 MB patients had lower recurrence rates and better 5-year relapse-free survival (RFP) compared with the SHH and G3 MB patients, among the four subgroups of MB. We found tumor-infiltrating B cells (TIL-Bs) enriched in the G4 subgroups in the Taiwanese MB patients and the SickKids cohort dataset. In the G4 subgroups, the patients with a high level of TIL-Bs had better 5-year overall survival. Mast cells presented in G4 MB tumors were positively correlated with TIL-Bs. Higher levels of CXCL13, IL-36γ, and CCL27 were found compared to other subgroups or normal brains. These three cytokines, B cells and mast cells contributed to the unique immune microenvironment in G4 MB tumors. Therefore, B-cell enrichment is a G4-subgroup-specific immune signature and the presence of B cells may be an indicator of a better prognosis in G4 MB patients. [ABSTRACT FROM AUTHOR]

Recently, immunotherapy targeting tumor-infiltrating lymphocytes (TILs) has emerged as a critical and promising treatment in several types of cancer. However, not all cancer types have been tested in immunotherapeutic trials, and different patients and cancer types may have unpredictable clinical outcomes. This situation has created a particular exigency for analyzing the prognostic significance of tumor-infiltrating T cells (TIL-T) and B cells (TIL-B) across different cancer types. To address the critical role of TILs, the abundances of TIL-T and TIL-B cells, as determined by the protein levels of LCK and CD20, were analyzed across heterogeneous human malignancies. TIL-T and TIL-B cells showed varying prognostic significances across heterogeneous cancer types. Additionally, distinct distributions of TILT and TIL-B cells were observed in different cancer and tumor microenvironment (TME) subtypes. Next, we analyzed the cellular context for the TME communication network involving the well-acknowledgeable chemokine receptors of TIL-T and TIL-B cells, implying the functional interactions with TME. Additionally, these chemokine receptors, expressed by TIL-T and TIL-B cells, were remarkably correlated with the levels of TIL-T or TIL-B cell infiltrations across nearly all the cancer types, indicating these chemokine receptors as universal targets for up- and down-regulating the TIL-T and TIL-B cells. Lastly, we provide the prognostic landscape of TIL-T and TIL-B cells across 30 cancer types and the subgroups defined by gender, histopathology, histological grade, therapeutic approach, drug, and TME subtype, which are intended to be a resource to fuel the investigations of TILs, with important implications for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer is a major global health problem. The type of malignant neoplasm and the potency of the immune response against tumors are two of the key factors influencing the outcome of the disease. The degree of tumor infiltration by lymphocytes plays an important role in antitumor response development, generally correlating with a favorable prognosis of treatment for certain cancers. We analyzed the abundance of tumor-infiltrating B cells (TIBs) in solid tumors of different cancers. TIBs were shown to be more abundant in colon and sigmoid colon cancer samples compared with cecal, rectal, and kidney cancer samples. The median and interquartile range of the TIB fraction were 11.5% and 4-20% in colon cancer, 6% and 3-11% in sigmoid colon cancer, 2.7% and 0.7-3.7% in cecal cancer, 2.5% and 0.9-3.6% in rectal cancer, 1.4% and 1.0-2.3% in kidney cancer, and 3.0% and 1.8-12% in lung cancer, respectively. However, there were no significant differences in the abundance of TIBs among samples at different stages of the cancer. Hence, investigation of the B cell response in colon cancer is of particular interest, since increased quantities of TIBs may indicate the existence of immunogenic tumor markers or the cell-cell interactions involved in disease progression. We believe that studying the diversity of TIBs in colon cancer will increaseour understanding of the mechanisms of the disease, contributing to the identification of new molecular targets for targeted oncotherapy., (Copyright ® 2024 National Research University Higher School of Economics.)

An important role for tumor infiltrating B lymphocytes (TIL-B) in the immune response to cancer is emerging; however, very little is known about the antigen specificity of antibodies produced in situ. The presence of IgA antibodies in the tumor microenvironment has been noted although their biological functions and clinical significance are unknown. This study used a 91-antigen microarray to examine the IgG and IgA autoantibody repertoires in breast cancer (BC). Tumor and adjacent breast tissue supernatants and plasma from BC patients together with normal breast tissue supernatants and plasma from healthy controls (patients undergoing mammary reduction and healthy blood donors) were analyzed to investigate relationships between autoantibodies and the clinical, histological and immunological features of tumors. Our data show that >84% of the BC samples tested contain autoantibodies to one or more antigens on the array, with ANKRD30BL, COPS4, and CTAG1B being most frequently reactive. Ex vivo TIL-B responses were uncoupled from systemic humoral responses in the majority of cases. A comparison of autoantibody frequencies in supernatants and plasma from patients and controls identified eight antigens that elicit BC-associated autoantibody responses. The overall prevalence of IgG and IgA autoantibodies was similar and while IgG and IgA responses were not linked they did correlate with distinct clinical, pathological and immunological features. Higher levels of ex vivo IgG responses to BC-associated antigens were associated with shorter recurrence-free survival (RFS), HER2 overexpression and lower tumor-infiltrating CD8+ T cell counts. Higher IgA levels were associated with estrogen and progesterone receptor-negative cancers but were not significantly associated with RFS. Furthermore, ex vivo IgA but not IgG autoantibodies reactive to BC-associated antigens were linked with germinal center and early memory B cell maturation and the presence of tertiary lymphoid structures suggesting that these TIL-B are activated in the tumor microenvironment. Overall, our results extend the current understanding of the antigen specificity, the biological and the clinical significance of IgG and IgA autoantibodies produced by BC TIL-B in situ.

An important role for tumor infiltrating B lymphocytes (TIL-B) in the immune response to cancer is emerging; however, very little is known about the antigen specificity of antibodies produced in situ. The presence of IgA antibodies in the tumor microenvironment has been noted although their biological functions and clinical significance are unknown. This study used a 91-antigen microarray to examine the IgG and IgA autoantibody repertoires in breast cancer (BC). Tumor and adjacent breast tissue supernatants and plasma from BC patients together with normal breast tissue supernatants and plasma from healthy controls (patients undergoing mammary reduction and healthy blood donors) were analyzed to investigate relationships between autoantibodies and the clinical, histological and immunological features of tumors. Our data show that >84% of the BC samples tested contain autoantibodies to one or more antigens on the array, with ANKRD30BL, COPS4, and CTAG1B being most frequently reactive. Ex vivo TIL-B responses were uncoupled from systemic humoral responses in the majority of cases. A comparison of autoantibody frequencies in supernatants and plasma from patients and controls identified eight antigens that elicit BC-associated autoantibody responses. The overall prevalence of IgG and IgA autoantibodies was similar and while IgG and IgA responses were not linked they did correlate with distinct clinical, pathological and immunological features. Higher levels of ex vivo IgG responses to BC-associated antigens were associated with shorter recurrence-free survival (RFS), HER2 overexpression and lower tumor-infiltrating CD8+ T cell counts. Higher IgA levels were associated with estrogen and progesterone receptor-negative cancers but were not significantly associated with RFS. Furthermore, ex vivo IgA but not IgG autoantibodies reactive to BC-associated antigens were linked with germinal center and early memory B cell maturation and the presence of tertiary lymphoid structures suggesting that these TIL-B are activated in the tumor microenvironment. Overall, our results extend the current understanding of the antigen specificity, the biological and the clinical significance of IgG and IgA autoantibodies produced by BC TIL-B in situ. [ABSTRACT FROM AUTHOR]

Recently, immunotherapy targeting tumor-infiltrating lymphocytes (TILs) has emerged as a critical and promising treatment in several types of cancer. However, not all cancer types have been tested in immunotherapeutic trials, and different patients and cancer types may have unpredictable clinical outcomes. This situation has created a particular exigency for analyzing the prognostic significance of tumor-infiltrating T cells (TIL-T) and B cells (TIL-B) across different cancer types. To address the critical role of TILs, the abundances of TIL-T and TIL-B cells, as determined by the protein levels of LCK and CD20, were analyzed across heterogeneous human malignancies. TIL-T and TIL-B cells showed varying prognostic significances across heterogeneous cancer types. Additionally, distinct distributions of TIL-T and TIL-B cells were observed in different cancer and tumor microenvironment (TME) subtypes. Next, we analyzed the cellular context for the TME communication network involving the well-acknowledgeable chemokine receptors of TIL-T and TIL-B cells, implying the functional interactions with TME. Additionally, these chemokine receptors, expressed by TIL-T and TIL-B cells, were remarkably correlated with the levels of TIL-T or TIL-B cell infiltrations across nearly all the cancer types, indicating these chemokine receptors as universal targets for up- and down-regulating the TIL-T and TIL-B cells. Lastly, we provide the prognostic landscape of TIL-T and TIL-B cells across 30 cancer types and the subgroups defined by gender, histopathology, histological grade, therapeutic approach, drug, and TME subtype, which are intended to be a resource to fuel the investigations of TILs, with important implications for cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Li, Liu, Zhang, Zhou, Jiang, Zhu, Yang, Tang and Chen.)

Several melanoma cell subpopulations with tumor-initiating and/or tumor-maintaining properties exist that may contribute to chemoresistance and tumor recurrence after standard therapies. One of these subpopulations expresses a B-cell marker, CD20. In a small pilot trial, we showed that a subset of Stage IV melanoma patients may potentially benefit from an adjuvant treatment using the anti-CD20 antibody rituximab. [ABSTRACT FROM AUTHOR]

High grade gliomas contribute to most brain tumor mortality. A few studies reported that the immune system affected glioma development, and immune biomarkers helped understand the disease and formulate effective immunotherapy for patients. Currently, no B lymphocyte-based prognostic signature was reported in gliomas. By applying 78 B cell lineage-specific genes, we conducted a whole-genome gene expression analysis in 782 high grade gliomas derived from three independent datasets by Cox regression analysis and risk score method for signature identification, and then used Gene Ontology, Gene Set Enrichment Analysis, and other statistical methods for functional annotations of the signature-defined differences. We developed a five B cell-associated gene signature for prognosis of high grade glioma patients, which is independent of clinicopathological and genetic features. The signature identified high risk patients suitable for chemoradiotherapy, whereas low risk patients should rule out chemotherapy with radiotherapy only. We found that tumors of TCGA Mesenchymal subtype and wild type IDH1 were preferentially stratified to the high risk group, which bore strong immunosuppressive microenvironment, while tumors of TCGA Proneural subtype and mutated IDH1 were significantly accumulated to the low risk group, which exhibited less immunosuppressive state. The five B cell-associated gene signature predicts poor survival of high risk patients bearing strong immunosuppression and helps select optimal therapeutic regimens for glioma patients.

Accumulating evidence indicated that B lymphocytes exerted complex functions in tumor immunity. On the one hand, B lymphocytes can inhibit tumor development through antibody generation, antigen presentation, tumor tissue interaction, and direct killing. On the other hand, B lymphocytes have tumor-promoting functions. A typical type of B lymphocytes, termed regulatory B cells, is confirmed to attenuate immune response in a tumor environment. In this paper, we summarize the current understanding of B-cell functions in tumor immunology, which may shed light on potential therapeutic strategies against cancer.

Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis. For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells. However, when considering the complex composition of the human immune system, recent findings of Nielsen et al on a potentially central role of tumor-infiltrating B cells is not really surprising. In this commentary article, I want to highlight the enormous potential impact of this observation for basic and translational research, prognostic procedures and ultimately for the development of future therapeutic concepts.