PDF(Pubmed)
Abstract：
Regulatory T cells (Tregs) play a crucial role in mediating immunosuppression in the tumor microenvironment. Furthermore, Tregs contribute to the lack of efficacy and hyperprogressive disease upon Programmed cell death protein 1 (PD-1) blockade immunotherapy. Thus, Tregs are considered a promising therapeutic target, especially when combined with PD-1 blockade. However, systemic depletion of Tregs causes severe autoimmune adverse events, which poses a serious challenge to Treg-directed therapy. Here, we developed a novel treatment to locally and predominantly damage Tregs by near-infrared duocarmycin photorelease (NIR-DPR). In this technology, we prepared anti-CD25 F(ab\')2 conjugates, which site-specifically uncage duocarmycin in CD25-expressing cells upon exposure to NIR light. In vitro, CD25-targeted NIR-DPR significantly increased apoptosis of CD25-expressing HT2-A5E cells. When tumors were irradiated with NIR light in vivo, intratumoral CD25+ Treg populations decreased and Ki-67 and Interleukin-10 expression was suppressed, indicating impaired functioning of intratumoral CD25+ Tregs. CD25-targeted NIR-DPR suppressed tumor growth and improved survival in syngeneic murine tumor models. Of note, CD25-targeted NIR-DPR synergistically enhanced the efficacy of PD-1 blockade, especially in tumors with higher CD8+/Treg PD-1 ratios. Furthermore, the combination therapy induced significant anti-cancer immunity including maturation of dendritic cells, extensive intratumoral infiltration of cytotoxic CD8+ T cells, and increased differentiation into CD8+ memory T cells. Altogether, CD25-targeted NIR-DPR locally and predominantly targets Tregs in the tumor microenvironment and synergistically improves the efficacy of PD-1 blockade, suggesting that this combination therapy can be a rational anti-cancer combination immunotherapy.
摘要：
调节性T细胞（Tregs）在介导肿瘤微环境中的免疫抑制中起着至关重要的作用。此外，Tregs导致程序性细胞死亡蛋白1（PD-1）阻断免疫疗法缺乏疗效和过度进行性疾病。因此，Tregs被认为是一个有希望的治疗靶点，特别是与PD-1阻断结合时。然而,Tregs的全身消耗会导致严重的自身免疫不良事件，这对Treg定向治疗提出了严峻挑战。这里,我们开发了一种新的治疗方法，通过近红外多卡霉素光释放（NIR-DPR）局部和主要损害Tregs。在这项技术中,我们制备了抗CD25F(ab')2偶联物，暴露于NIR光后，在表达CD25的细胞中位点特异性地捕获多卡霉素。体外，CD25靶向的NIR-DPR显著增加表达CD25的HT2-A5E细胞的凋亡。当肿瘤在体内用NIR光照射时，肿瘤内CD25+Treg群体减少，Ki-67和白细胞介素-10表达受到抑制，提示肿瘤内CD25+Tregs功能受损。CD25靶向的NIR-DPR抑制肿瘤生长并改善同系小鼠肿瘤模型的存活率。值得注意的是，CD25靶向NIR-DPR协同增强PD-1阻断的疗效，尤其是在CD8+/TregPD-1比例较高的肿瘤中。此外，联合疗法诱导显著的抗癌免疫，包括树突状细胞的成熟，细胞毒性CD8+T细胞的广泛肿瘤内浸润，和增加分化为CD8+记忆T细胞。总之,CD25靶向的NIR-DPR局部和主要靶向肿瘤微环境中的Treg，并协同提高PD-1阻断的疗效，表明这种联合疗法可以是一种合理的抗癌联合免疫疗法。
