Specifically blocking [alpha]v[beta]8-mediated TGF-[beta] signaling to reverse immunosuppression by modulating macrophage polarization

• Published in: Journal of experimental & clinical cancer research Vol. 44; no. 1
• Main Authors: Guo, Cuicui, Sun, Hui, Du, Yulei, Dai, Xiaodong, Pang, Yu, Han, Zhen, Xiong, Xinhui, Li, Shaowei, Zhang, Junhua, Zheng, Qingbing, Gui, Xun
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 02.01.2025
• Subjects: Antibodies; Immunotherapy; Integrins; Macrophages; RNA sequencing; Transforming growth factors; Tumors; Viral antibodies; United States; China
• ISSN: 0392-9078
• DOI: 10.1186/s13046-024-03250-1

Background Targeting the TGF-[beta] pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-[beta]. Integrin [alpha]v[beta]8, a pivotal activator of TGF-[beta], has been implicated in TGF-[beta] signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-[alpha]v[beta]8 antibodies. Nevertheless, the expression profile of [alpha]v[beta]8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-[alpha]v[beta]8 antibodies are not yet fully elucidated. Methods We utilized single-cell RNA sequencing to assess [alpha]v[beta]8 expression across various human tumors. An anti-[alpha]v[beta]8 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 [alpha]v[beta]8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of [alpha]v[beta]8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate [alpha]v[beta]8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the [alpha]v[beta]8 antibody were conducted in cynomolgus monkeys. Results Integrin [alpha]v[beta]8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific [alpha]v[beta]8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the [beta]8 subunit, without binding to the [alpha]v 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 [alpha]v[beta]8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated [alpha]v[beta]8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys. Conclusions In summary, integrin [alpha]v[beta]8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting [alpha]v[beta]8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining [alpha]v[beta]8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of [alpha]v[beta]8 antibodies. Graphical abstract Keywords: TGF-[beta], Tumor microenvironment, Macrophage polarization, Immune cell infiltration