Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma
Abstract Objective Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, with significant clinical heterogeneity. Recent studies suggest that the intratumoral microbiome may influence the tumor microenvironment, affecting patient prognosis and therapeutic response...
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Springer
2025-03-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-03972-x |
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| author | Zheng Yijia Xiaoyu Li Lina Ma Siying Wang Hong Du Yun Wu Jing Yu Yunxia Xiang Daiqin Xiong Huiting Shan Yubo Wang Zhi Wang Jianping Hao Jie Wang |
| author_facet | Zheng Yijia Xiaoyu Li Lina Ma Siying Wang Hong Du Yun Wu Jing Yu Yunxia Xiang Daiqin Xiong Huiting Shan Yubo Wang Zhi Wang Jianping Hao Jie Wang |
| author_sort | Zheng Yijia |
| collection | DOAJ |
| description | Abstract Objective Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, with significant clinical heterogeneity. Recent studies suggest that the intratumoral microbiome may influence the tumor microenvironment, affecting patient prognosis and therapeutic responses. This study aims to identify microbiome-related subtypes in DLBCL and assess their impact on prognosis, immune infiltration, and therapeutic sensitivity. Methods Transcriptomic and microbiome data from 48 DLBCL patients were obtained from public databases. Consensus clustering was used to classify patients into distinct microbiome-related subtypes. Functional enrichment analysis, immune infiltration assessments, and single-cell RNA sequencing were performed to explore the biological characteristics of these subtypes. Drug sensitivity predictions were made using the OncoPredict tool. Hub genes’ expression and biological function were validated and inferred in cell lines and independent cohorts of DLBCL. Results Two distinct microbiome-related subtypes were identified. Patients in Cluster 1 exhibited significantly better overall survival (P < 0.05), with higher immune infiltration of regulatory T cells and M0 macrophages compared to Cluster 2, which was associated with poorer outcomes. Functional enrichment analysis revealed that genes in Cluster 1 were involved in immune regulatory pathways, including cytokine–cytokine receptor interactions and chemokine signaling, suggesting enhanced anti-tumor immune responses. In contrast, genes in Cluster 2 were enriched in immunosuppressive pathways, contributing to a less favorable prognosis. Single-cell RNA sequencing analysis revealed significant heterogeneity in immune cell populations within the tumor microenvironment. B cells exhibited the most notable heterogeneity, as indicated by stemness and differentiation potential scoring. Intercellular communication analysis demonstrated that B cells played a key role in immune cell interactions, with significant differences observed in MIF signaling between B-cell subgroups. Pseudo-time analysis further revealed distinct differentiation trajectories of B cells, highlighting their potential heterogeneity across different immune environments. Metabolic pathway analysis showed significant differences in the average expression levels of metabolic pathways among B-cell subgroups, suggesting functional specialization. Furthermore, interaction analysis between core genes involved in B-cell differentiation and microbiome-driven differentially expressed genes identified nine common genes (GSTM5, LURAP1, LINC02802, MAB21L3, C2CD4D, MMEL1, TSPAN2, and CITED4), which were found to play critical roles in B-cell differentiation and were influenced by the intratumoral microbiome. DLBCL cell lines and clinical cohorts validated that MMEL1 and CITED4 with important biologically function in DLBCL cell survival and subtype classification. Conclusions This study demonstrates the prognostic significance of the intratumoral microbiome in DLBCL, identifying distinct microbiome-related subtypes that impact immune infiltration, metabolic activity, and therapeutic responses. The findings provide insights into the immune heterogeneity within the tumor microenvironment, focusing on B cells and their differentiation dynamics. These results lay the foundation for microbiome-based prognostic biomarkers and personalized treatment approaches, ultimately aiming to enhance patient outcomes in DLBCL. |
| format | Article |
| id | doaj-art-b8ccd75f2cbb4288ad3f5324cc8596d1 |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-b8ccd75f2cbb4288ad3f5324cc8596d12025-08-20T02:49:23ZengSpringerCancer Immunology, Immunotherapy1432-08512025-03-0174412110.1007/s00262-025-03972-xIdentification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphomaZheng Yijia0Xiaoyu Li1Lina Ma2Siying Wang3Hong Du4Yun Wu5Jing Yu6Yunxia Xiang7Daiqin Xiong8Huiting Shan9Yubo Wang10Zhi Wang11Jianping Hao12Jie Wang13School of Pharmacy, Xinjiang Medical UniversitySchool of Pharmacy, Xinjiang Medical UniversitySchool of Pharmacy, Xinjiang Medical UniversitySchool of Pharmacy, Xinjiang Medical UniversitySchool of Pharmacy, Xinjiang Medical UniversityDepartment of General Medicine, The First Affiliated Hospital of the Xinjiang Medical UniversitySchool of Pharmacy, Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Haematology, The First Affiliated Hospital of the Xinjiang Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital of Xinjiang Medical UniversityAbstract Objective Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, with significant clinical heterogeneity. Recent studies suggest that the intratumoral microbiome may influence the tumor microenvironment, affecting patient prognosis and therapeutic responses. This study aims to identify microbiome-related subtypes in DLBCL and assess their impact on prognosis, immune infiltration, and therapeutic sensitivity. Methods Transcriptomic and microbiome data from 48 DLBCL patients were obtained from public databases. Consensus clustering was used to classify patients into distinct microbiome-related subtypes. Functional enrichment analysis, immune infiltration assessments, and single-cell RNA sequencing were performed to explore the biological characteristics of these subtypes. Drug sensitivity predictions were made using the OncoPredict tool. Hub genes’ expression and biological function were validated and inferred in cell lines and independent cohorts of DLBCL. Results Two distinct microbiome-related subtypes were identified. Patients in Cluster 1 exhibited significantly better overall survival (P < 0.05), with higher immune infiltration of regulatory T cells and M0 macrophages compared to Cluster 2, which was associated with poorer outcomes. Functional enrichment analysis revealed that genes in Cluster 1 were involved in immune regulatory pathways, including cytokine–cytokine receptor interactions and chemokine signaling, suggesting enhanced anti-tumor immune responses. In contrast, genes in Cluster 2 were enriched in immunosuppressive pathways, contributing to a less favorable prognosis. Single-cell RNA sequencing analysis revealed significant heterogeneity in immune cell populations within the tumor microenvironment. B cells exhibited the most notable heterogeneity, as indicated by stemness and differentiation potential scoring. Intercellular communication analysis demonstrated that B cells played a key role in immune cell interactions, with significant differences observed in MIF signaling between B-cell subgroups. Pseudo-time analysis further revealed distinct differentiation trajectories of B cells, highlighting their potential heterogeneity across different immune environments. Metabolic pathway analysis showed significant differences in the average expression levels of metabolic pathways among B-cell subgroups, suggesting functional specialization. Furthermore, interaction analysis between core genes involved in B-cell differentiation and microbiome-driven differentially expressed genes identified nine common genes (GSTM5, LURAP1, LINC02802, MAB21L3, C2CD4D, MMEL1, TSPAN2, and CITED4), which were found to play critical roles in B-cell differentiation and were influenced by the intratumoral microbiome. DLBCL cell lines and clinical cohorts validated that MMEL1 and CITED4 with important biologically function in DLBCL cell survival and subtype classification. Conclusions This study demonstrates the prognostic significance of the intratumoral microbiome in DLBCL, identifying distinct microbiome-related subtypes that impact immune infiltration, metabolic activity, and therapeutic responses. The findings provide insights into the immune heterogeneity within the tumor microenvironment, focusing on B cells and their differentiation dynamics. These results lay the foundation for microbiome-based prognostic biomarkers and personalized treatment approaches, ultimately aiming to enhance patient outcomes in DLBCL.https://doi.org/10.1007/s00262-025-03972-xDiffuse large B-cell lymphomaIntratumoral microbiomeImmune infiltrationTumor microenvironmentPersonalized medicine |
| spellingShingle | Zheng Yijia Xiaoyu Li Lina Ma Siying Wang Hong Du Yun Wu Jing Yu Yunxia Xiang Daiqin Xiong Huiting Shan Yubo Wang Zhi Wang Jianping Hao Jie Wang Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma Cancer Immunology, Immunotherapy Diffuse large B-cell lymphoma Intratumoral microbiome Immune infiltration Tumor microenvironment Personalized medicine |
| title | Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma |
| title_full | Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma |
| title_fullStr | Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma |
| title_full_unstemmed | Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma |
| title_short | Identification of intratumoral microbiome-driven immune modulation and therapeutic implications in diffuse large B-cell lymphoma |
| title_sort | identification of intratumoral microbiome driven immune modulation and therapeutic implications in diffuse large b cell lymphoma |
| topic | Diffuse large B-cell lymphoma Intratumoral microbiome Immune infiltration Tumor microenvironment Personalized medicine |
| url | https://doi.org/10.1007/s00262-025-03972-x |
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