Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization
Abstract Background Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of...
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03250-1 |
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| author | Cuicui Guo Hui Sun Yulei Du Xiaodong Dai Yu Pang Zhen Han Xinhui Xiong Shaowei Li Junhua Zhang Qingbing Zheng Xun Gui |
| author_facet | Cuicui Guo Hui Sun Yulei Du Xiaodong Dai Yu Pang Zhen Han Xinhui Xiong Shaowei Li Junhua Zhang Qingbing Zheng Xun Gui |
| author_sort | Cuicui Guo |
| collection | DOAJ |
| description | Abstract Background Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated. Methods We utilized single-cell RNA sequencing to assess αvβ8 expression across various human tumors. An anti-αvβ8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between αvβ8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of αvβ8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate αvβ8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the αvβ8 antibody were conducted in cynomolgus monkeys. Results Integrin αvβ8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific αvβ8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the β8 subunit, without binding to the αv subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high αvβ8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated αvβ8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys. Conclusions In summary, integrin αvβ8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting αvβ8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining αvβ8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of αvβ8 antibodies. Graphical abstract |
| format | Article |
| id | doaj-art-62085004b22b4ae5b39a8492950accbc |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-62085004b22b4ae5b39a8492950accbc2025-01-05T12:50:03ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111910.1186/s13046-024-03250-1Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarizationCuicui Guo0Hui Sun1Yulei Du2Xiaodong Dai3Yu Pang4Zhen Han5Xinhui Xiong6Shaowei Li7Junhua Zhang8Qingbing Zheng9Xun Gui10Mabwell (Shanghai) Bioscience Co., LtdState Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen UniversityMabwell (Shanghai) Bioscience Co., LtdMabwell (Shanghai) Bioscience Co., LtdMabwell (Shanghai) Bioscience Co., LtdMabwell (Shanghai) Bioscience Co., LtdNanjing Novoacine Biotechnology Co., LtdState Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen UniversityDepartment of Radiation Oncology, Fudan University Shanghai Cancer CenterState Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen UniversityMabwell (Shanghai) Bioscience Co., LtdAbstract Background Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated. Methods We utilized single-cell RNA sequencing to assess αvβ8 expression across various human tumors. An anti-αvβ8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between αvβ8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of αvβ8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate αvβ8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the αvβ8 antibody were conducted in cynomolgus monkeys. Results Integrin αvβ8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific αvβ8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the β8 subunit, without binding to the αv subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high αvβ8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated αvβ8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys. Conclusions In summary, integrin αvβ8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting αvβ8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining αvβ8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of αvβ8 antibodies. Graphical abstracthttps://doi.org/10.1186/s13046-024-03250-1TGF-βTumor microenvironmentMacrophage polarizationImmune cell infiltration |
| spellingShingle | Cuicui Guo Hui Sun Yulei Du Xiaodong Dai Yu Pang Zhen Han Xinhui Xiong Shaowei Li Junhua Zhang Qingbing Zheng Xun Gui Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization Journal of Experimental & Clinical Cancer Research TGF-β Tumor microenvironment Macrophage polarization Immune cell infiltration |
| title | Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization |
| title_full | Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization |
| title_fullStr | Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization |
| title_full_unstemmed | Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization |
| title_short | Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization |
| title_sort | specifically blocking αvβ8 mediated tgf β signaling to reverse immunosuppression by modulating macrophage polarization |
| topic | TGF-β Tumor microenvironment Macrophage polarization Immune cell infiltration |
| url | https://doi.org/10.1186/s13046-024-03250-1 |
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