<br>双功能 iRGD-抗 CD3 通过促进肿瘤浸润和 T 细胞激活来增强 T 细胞的抗肿瘤效力。,Journal for ImmunoTherapy of Cancer

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双功能 iRGD-抗 CD3 通过促进肿瘤浸润和 T 细胞激活来增强 T 细胞的抗肿瘤效力。
Journal for ImmunoTherapy of Cancer ( IF 10.3 ) Pub Date : 2021-05-01 , DOI: 10.1136/jitc-2020-001925
Shujuan Zhou ₁ , Fanyan Meng ₁ , Shiyao Du ₁ , Hanqing Qian ₁ , Naiqing Ding ₁ , Huizi Sha ₁ , Mei Zhu ₁ , Xiaoxiao Yu ₁ , Lifeng Wang ₁ , Baorui Liu ₂ , Jia Wei ₂

Affiliation

背景转移的T细胞浸润不良和活化有限是阻碍实体瘤过继细胞免疫疗法发展的根本因素。肿瘤穿透肽 iRGD 已被广泛用于将药物输送到肿瘤组织深处。 CD3 靶向双特异性抗体代表了一种有前途的免疫疗法，它可以招募并激活 T 细胞。方法使用共聚焦显微镜在肿瘤球体中证明 T 细胞渗透，并通过组织学和体内实时荧光成像在异种移植肿瘤中证明 T 细胞渗透。通过流式细胞术和共聚焦显微镜评估T细胞的活化和细胞毒性。生物发光成像用于评估体内抗肿瘤作用，透射电子显微镜用于机理研究。结果我们生成了一种新型双功能试剂 iRGD-anti-CD3，它可以通过 CD3 接合将 iRGD 固定在 T 细胞表面。我们发现 iRGD-抗 CD3 修饰不仅促进 T 细胞在 3D 肿瘤球体和异种移植肿瘤结节中的浸润，而且还诱导 T 细胞活化和针对靶癌细胞的细胞毒性。在几种异种移植小鼠模型中，用 iRGD-anti-CD3 修饰的 T 细胞显着抑制肿瘤生长并延长生存期，结合程序性细胞死亡蛋白 1 (PD-1) 阻断可进一步增强这种作用。机制研究表明，iRGD-抗-CD3 启动内皮细胞质中称为囊泡空泡细胞器的运输途径，以促进 T 细胞外渗。结论总而言之，我们表明 iRGD-抗 CD3 修饰是一种创新的双功能策略，可以克服过继细胞疗法的主要瓶颈。此外，我们证明与 PD-1 阻断相结合可以进一步提高 iRGD-抗-CD3 修饰 T 细胞的抗肿瘤功效。

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Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation.

BACKGROUND Poor infiltration and limited activation of transferred T cells are fundamental factors impeding the development of adoptive cell immunotherapy in solid tumors. A tumor-penetrating peptide iRGD has been widely used to deliver drugs deep into tumor tissues. CD3-targeting bispecific antibodies represent a promising immunotherapy which recruits and activates T cells. METHODS T-cell penetration was demonstrated in tumor spheroids using confocal microscope, and in xenografted tumors by histology and in vivo real-time fluorescence imaging. Activation and cytotoxicity of T cells were assessed by flow cytometry and confocal microscope. Bioluminescence imaging was used to evaluate in vivo antitumor effects, and transmission electron microscopy was used for mechanistic studies. RESULTS We generated a novel bifunctional agent iRGD-anti-CD3 which could immobilize iRGD on the surface of T cells through CD3 engaging. We found that iRGD-anti-CD3 modification not only facilitated T-cell infiltration in 3D tumor spheroids and xenografted tumor nodules but also induced T-cell activation and cytotoxicity against target cancer cells. T cells modified with iRGD-anti-CD3 significantly inhibited tumor growth and prolonged survival in several xenograft mouse models, which was further enhanced by the combination of programmed cell death protein 1 (PD-1) blockade. Mechanistic studies revealed that iRGD-anti-CD3 initiated a transport pathway called vesiculovacuolar organelles in the endothelial cytoplasm to promote T-cell extravasation. CONCLUSION Altogether, we show that iRGD-anti-CD3 modification is an innovative and bifunctional strategy to overcome major bottlenecks in adoptive cell therapy. Moreover, we demonstrate that combination with PD-1 blockade can further improve antitumor efficacy of iRGD-anti-CD3-modified T cells.

更新日期：2021-05-01

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