PDF(Pubmed)
Abstract：
Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells. In this study, using a novel bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonism induces potent antitumor immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Tregs into both fragile Foxp3+ IFNγ+ Tregs with decreased suppressive function and lineage-instable Foxp3- IFNγ+ ex-Tregs. Treg fragility is partially driven by IFNγ signaling, whereas Treg instability is associated with reduced IL2 responsiveness upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Tregs and their progeny partially reverses the antitumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Tregs into IFNγ-producing cells contributes to the anti-tumor efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting costimulatory receptors highly expressed by Tregs potentiate antitumor immunity in mouse models.
UNASSIGNED: The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.
UNASSIGNED: The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.
摘要：
调节性T(Treg)细胞在许多肿瘤中高度富集并抑制对癌症的免疫应答。对重编程Treg细胞以促进抗肿瘤免疫存在强烈的兴趣。OX40和CD137在Treg细胞上高度表达，激活和记忆T细胞，NK细胞这里,使用靶向小鼠OX40和CD137（FS120m）的新型四价双特异性抗体，我们显示OX40/CD137双特异性激动剂部分依赖于功能性重编程的Treg细胞产生IFN-γ诱导有效的抗肿瘤免疫。用OX40/CD137双特异性激动剂治疗荷瘤动物将Treg细胞重新编程为具有降低的抑制功能的脆性Foxp3IFN-γ细胞，和谱系不稳定的Foxp3-IFN-γ+细胞。Treg细胞脆性部分依赖于IFN-γ信号,而Treg细胞不稳定性与OX40/CD137双特异性激动剂治疗后IL-2信号传导降低有关。重要的是,Foxp3+Treg细胞及其后代中Ifng的条件性缺失部分逆转了OX40/CD137双特异性激动剂治疗的抗肿瘤功效，揭示Treg细胞重编程为产生IFN-γ的细胞有助于OX40/CD137双特异性激动剂的功效。这些发现提供了对靶向由Treg细胞高度表达的共刺激受体的双特异性激动剂疗法增强小鼠模型中的抗肿瘤免疫的机制的见解。
