Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity
Abstract Background Regulatory B cells (Bregs), a specialized subset of B cells that modulate immune responses and maintain immune tolerance in malignant tumors, have not been extensively investigated in the context of bladder cancer (BLCA). This study aims to elucidate the roles of Bregs and Breg-r...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-03017-8 |
| _version_ | 1797219541714993152 |
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| author | Jiawei Zhou Ranran Zhou Yuanchao Zhu Shikai Deng Bahaerguli Muhuitijiang Chengyao Li Xiaojun Shi Ling Zhang Wanlong Tan |
| author_facet | Jiawei Zhou Ranran Zhou Yuanchao Zhu Shikai Deng Bahaerguli Muhuitijiang Chengyao Li Xiaojun Shi Ling Zhang Wanlong Tan |
| author_sort | Jiawei Zhou |
| collection | DOAJ |
| description | Abstract Background Regulatory B cells (Bregs), a specialized subset of B cells that modulate immune responses and maintain immune tolerance in malignant tumors, have not been extensively investigated in the context of bladder cancer (BLCA). This study aims to elucidate the roles of Bregs and Breg-related genes in BLCA. Methods We assessed Breg infiltration levels in 34 pairs of BLCA and corresponding paracancerous tissues using immunohistochemical staining. We conducted transwell and wound healing assays to evaluate the impact of Bregs on the malignant phenotype of SW780 and T24 cells. Breg-related genes were identified through gene sets and transcriptional analysis. The TCGA-BLCA cohort served as the training set, while the IMvigor210 and 5 GEO cohorts were used as external validation sets. We employed LASSO regression and random forest for feature selection and developed a risk signature using Cox regression. Primary validation of the risk signature was performed through immunohistochemical staining and RT-qPCR experiments using the 34 local BLCA samples. Additionally, we employed transfection assays and flow cytometry to investigate Breg expansion ability and immunosuppressive functions. Results Breg levels in BLCA tissues were significantly elevated compared to paracancerous tissues (P < 0.05) and positively correlated with tumor malignancy (P < 0.05). Co-incubation of SW780 and T24 cells with Bregs resulted in enhanced invasion and migration abilities (all P < 0.05). We identified 27 Breg-related genes, including CD96, OAS1, and CSH1, which were integrated into the risk signature. This signature demonstrated robust prognostic classification across the 6 cohorts (pooled HR = 2.25, 95% CI = 1.52–3.33). Moreover, the signature exhibited positive associations with advanced tumor stage (P < 0.001) and Breg infiltration ratios (P < 0.05) in the local samples. Furthermore, the signature successfully predicted immunotherapeutic sensitivity in three cohorts (all P < 0.05). Knockdown of CSH1 in B cells increased Breg phenotype and enhanced suppressive ability against CD8 + T cells (all P < 0.05). Conclusions Bregs play a pro-tumor role in the development of BLCA. The Breg-related gene signature established in this study holds great potential as a valuable tool for evaluating prognosis and predicting immunotherapeutic response in BLCA patients. |
| first_indexed | 2024-04-24T12:35:17Z |
| format | Article |
| id | doaj.art-95a8792a0d4a48e5b37db06cdd570b2d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-24T12:35:17Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-95a8792a0d4a48e5b37db06cdd570b2d2024-04-07T11:34:23ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-04-0143111910.1186/s13046-024-03017-8Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivityJiawei Zhou0Ranran Zhou1Yuanchao Zhu2Shikai Deng3Bahaerguli Muhuitijiang4Chengyao Li5Xiaojun Shi6Ling Zhang7Wanlong Tan8Department of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityAbstract Background Regulatory B cells (Bregs), a specialized subset of B cells that modulate immune responses and maintain immune tolerance in malignant tumors, have not been extensively investigated in the context of bladder cancer (BLCA). This study aims to elucidate the roles of Bregs and Breg-related genes in BLCA. Methods We assessed Breg infiltration levels in 34 pairs of BLCA and corresponding paracancerous tissues using immunohistochemical staining. We conducted transwell and wound healing assays to evaluate the impact of Bregs on the malignant phenotype of SW780 and T24 cells. Breg-related genes were identified through gene sets and transcriptional analysis. The TCGA-BLCA cohort served as the training set, while the IMvigor210 and 5 GEO cohorts were used as external validation sets. We employed LASSO regression and random forest for feature selection and developed a risk signature using Cox regression. Primary validation of the risk signature was performed through immunohistochemical staining and RT-qPCR experiments using the 34 local BLCA samples. Additionally, we employed transfection assays and flow cytometry to investigate Breg expansion ability and immunosuppressive functions. Results Breg levels in BLCA tissues were significantly elevated compared to paracancerous tissues (P < 0.05) and positively correlated with tumor malignancy (P < 0.05). Co-incubation of SW780 and T24 cells with Bregs resulted in enhanced invasion and migration abilities (all P < 0.05). We identified 27 Breg-related genes, including CD96, OAS1, and CSH1, which were integrated into the risk signature. This signature demonstrated robust prognostic classification across the 6 cohorts (pooled HR = 2.25, 95% CI = 1.52–3.33). Moreover, the signature exhibited positive associations with advanced tumor stage (P < 0.001) and Breg infiltration ratios (P < 0.05) in the local samples. Furthermore, the signature successfully predicted immunotherapeutic sensitivity in three cohorts (all P < 0.05). Knockdown of CSH1 in B cells increased Breg phenotype and enhanced suppressive ability against CD8 + T cells (all P < 0.05). Conclusions Bregs play a pro-tumor role in the development of BLCA. The Breg-related gene signature established in this study holds great potential as a valuable tool for evaluating prognosis and predicting immunotherapeutic response in BLCA patients.https://doi.org/10.1186/s13046-024-03017-8Bladder cancerRegulatory B cellsGene signaturePrognosisImmunotherapy |
| spellingShingle | Jiawei Zhou Ranran Zhou Yuanchao Zhu Shikai Deng Bahaerguli Muhuitijiang Chengyao Li Xiaojun Shi Ling Zhang Wanlong Tan Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity Journal of Experimental & Clinical Cancer Research Bladder cancer Regulatory B cells Gene signature Prognosis Immunotherapy |
| title | Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity |
| title_full | Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity |
| title_fullStr | Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity |
| title_full_unstemmed | Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity |
| title_short | Investigating the impact of regulatory B cells and regulatory B cell-related genes on bladder cancer progression and immunotherapeutic sensitivity |
| title_sort | investigating the impact of regulatory b cells and regulatory b cell related genes on bladder cancer progression and immunotherapeutic sensitivity |
| topic | Bladder cancer Regulatory B cells Gene signature Prognosis Immunotherapy |
| url | https://doi.org/10.1186/s13046-024-03017-8 |
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