Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma
Abstract: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by distinct morphological, genetic, and clinical features. DLBCL with Myc/Bcl-2 double expression (DE) has been positively correlated with poor prognosis and a low response rate to chemotherapy. However, molecul...
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Elsevier
2025-07-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S247395292500223X |
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| author | Bo Zhang Yaping Xie Minmin Shen Jianai Sun Yue Li Jing Zhang Qi Li Chuanghua Chen Zhenzhen Chen Wei Wang Jingcheng Wu Zhan Zhou Jianhua Fang Youyou Yan Shenxian Qian Xiangmin Tong Nengming Lin Hongyan Tong |
| author_facet | Bo Zhang Yaping Xie Minmin Shen Jianai Sun Yue Li Jing Zhang Qi Li Chuanghua Chen Zhenzhen Chen Wei Wang Jingcheng Wu Zhan Zhou Jianhua Fang Youyou Yan Shenxian Qian Xiangmin Tong Nengming Lin Hongyan Tong |
| author_sort | Bo Zhang |
| collection | DOAJ |
| description | Abstract: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by distinct morphological, genetic, and clinical features. DLBCL with Myc/Bcl-2 double expression (DE) has been positively correlated with poor prognosis and a low response rate to chemotherapy. However, molecular mechanisms underlying the malignant progression of DE DLBCL and the tumor microenvironment of DE DLBCL have not been fully elucidated. In this study, we assessed protein expression in samples from 18 patients with DLBCL using imaging mass cytometry with a panel of 26 metal-tagged antibodies, identifying 8 cell types within the tumor microenvironment. Although the ratio of immune cells did not significantly differ between DE and non-DE tissues, a strong interaction between fibroblasts and exhausted CD8+ T cells was specifically observed in DE tissues. By comparing protein expression ratios between DE and non-DE tissues, we found that p-S6 levels were significantly higher in B cells and fibroblasts of DE samples than non-DE samples. In our retrospective study, p-S6 independently predicted an inferior prognosis in patients with DLBCL (n = 71; hazard ratio, 5.758; 95% confidence interval, 1.297-25.558; P = .021). In addition, coculture with fibroblasts accelerated the in vitro and in vivo growth of DLBCL cells, and enrichment of the mammalian target of rapamycin/S6 pathways was identified using bulk RNA sequencing. Conversely, specific inhibition of p-S6 suppressed DLBCL cell proliferation and exhibited synergistic effects with chemotherapy in vivo. In summary, our findings elucidated the specific tumor microenvironment in DE DLBCL tissues and identified p-S6 as a promising therapeutic target to enhance the efficacy of chemotherapy. |
| format | Article |
| id | doaj-art-3e080acc508744e0b07bb0898712133e |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-3e080acc508744e0b07bb0898712133e2025-08-20T03:24:08ZengElsevierBlood Advances2473-95292025-07-019133249326210.1182/bloodadvances.2024015469Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphomaBo Zhang0Yaping Xie1Minmin Shen2Jianai Sun3Yue Li4Jing Zhang5Qi Li6Chuanghua Chen7Zhenzhen Chen8Wei Wang9Jingcheng Wu10Zhan Zhou11Jianhua Fang12Youyou Yan13Shenxian Qian14Xiangmin Tong15Nengming Lin16Hongyan Tong17School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, ChinaDepartment of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; Department of Drug Clinical Trial Institution, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, ChinaDepartment of Hematology, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaDepartment of Ultrasound, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, ChinaDepartment of Pathology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaInnovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaInnovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaDepartment of Ultrasound, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaDepartment of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China; Shenxian Qian, Department of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, #261 Huansha Road, Hangzhou 310006, China;Department of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China; Xiangmin Tong, Department of Hematology, Hangzhou First People’s Hospital, Westlake University School of Medicine, #261 Huansha Road, Hangzhou, China;School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Nengming Lin, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Westlake University School of Medicine, #261 Huansha Road, Hangzhou 310006, China;Department of Hematology, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Correspondence: Hongyan Tong, Department of Hematology, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, The First Affiliated Hospital, Cancer Center, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou, China;Abstract: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by distinct morphological, genetic, and clinical features. DLBCL with Myc/Bcl-2 double expression (DE) has been positively correlated with poor prognosis and a low response rate to chemotherapy. However, molecular mechanisms underlying the malignant progression of DE DLBCL and the tumor microenvironment of DE DLBCL have not been fully elucidated. In this study, we assessed protein expression in samples from 18 patients with DLBCL using imaging mass cytometry with a panel of 26 metal-tagged antibodies, identifying 8 cell types within the tumor microenvironment. Although the ratio of immune cells did not significantly differ between DE and non-DE tissues, a strong interaction between fibroblasts and exhausted CD8+ T cells was specifically observed in DE tissues. By comparing protein expression ratios between DE and non-DE tissues, we found that p-S6 levels were significantly higher in B cells and fibroblasts of DE samples than non-DE samples. In our retrospective study, p-S6 independently predicted an inferior prognosis in patients with DLBCL (n = 71; hazard ratio, 5.758; 95% confidence interval, 1.297-25.558; P = .021). In addition, coculture with fibroblasts accelerated the in vitro and in vivo growth of DLBCL cells, and enrichment of the mammalian target of rapamycin/S6 pathways was identified using bulk RNA sequencing. Conversely, specific inhibition of p-S6 suppressed DLBCL cell proliferation and exhibited synergistic effects with chemotherapy in vivo. In summary, our findings elucidated the specific tumor microenvironment in DE DLBCL tissues and identified p-S6 as a promising therapeutic target to enhance the efficacy of chemotherapy.http://www.sciencedirect.com/science/article/pii/S247395292500223X |
| spellingShingle | Bo Zhang Yaping Xie Minmin Shen Jianai Sun Yue Li Jing Zhang Qi Li Chuanghua Chen Zhenzhen Chen Wei Wang Jingcheng Wu Zhan Zhou Jianhua Fang Youyou Yan Shenxian Qian Xiangmin Tong Nengming Lin Hongyan Tong Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma Blood Advances |
| title | Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma |
| title_full | Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma |
| title_fullStr | Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma |
| title_full_unstemmed | Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma |
| title_short | Multiplexed imaging mass cytometry elicits p-S6 as a therapeutic and prognostic factor in diffuse large B-cell lymphoma |
| title_sort | multiplexed imaging mass cytometry elicits p s6 as a therapeutic and prognostic factor in diffuse large b cell lymphoma |
| url | http://www.sciencedirect.com/science/article/pii/S247395292500223X |
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