Dynamic Biomaterials for Cancer Immunotherapy, Max Planck Partner Group, Institute of Materials Science of Barcelona (ICMAB-CSIC) , Campus UAB, Bellaterra, E-08193, Spain.
Department of Molecular Nanoscience and Organic Materials, Institute of Materials Science of Barcelona (ICMAB-CSIC) and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , Campus UAB, Bellaterra, E-08193, Spain.
Nano Lett. 2017 Oct 11;17(10):6110-6116. doi: 10.1021/acs.nanolett.7b02636. Epub 2017 Sep 6.
Adoptive cell therapy (ACT) has shown very promising results as treatment for cancer in a few clinical trials, such as the complete remissions of otherwise terminal leukemia patients. Nevertheless, the introduction of ACT into clinics requires overcoming not only medical but also technical challenges, such as the ex vivo expansion of large amounts of specific T-cells. Nanostructured surfaces represent a novel T-cell stimulation technique that enables us to fine-tune the density and orientation of activating molecules presented to the cells. In this work, we studied the influence of integrin-mediated cell-adhesion on T-cell activation, proliferation, and differentiation using nanostructured surfaces, which provide a well-defined system at the nanoscale compared with standard cultures. Specifically, we synthesized a polymeric polyethylene glycol (PEG) hydrogel cross-linked with two fibronectin-derived peptides, cyclic Arg-Gly-Asp (cRGD) and cyclic Leu-Asp-Val (cLDV), that are known to activate different integrins. Moreover, the hydrogels were decorated with a quasi-hexagonal array of gold nanoparticles (AuNPs) functionalized with the activating antibody CD3 to initiate T-cell activation. Both cLDV and cRGD hydrogels showed higher T-cell activation (CD69 expression and IL-2 secretion) than nonfunctionalized PEG hydrogels. However, only the cRGD hydrogels clearly supported proliferation giving a higher proportion of cells with memory (CD4CD45RO) than naı̈ve (CD4CD45RA) phenotypes when interparticle distances smaller than 150 nm were used. Thus, T-cell proliferation can be enhanced by the activation of integrins through the RGD sequence.
过继细胞疗法（ACT）在几项临床试验中显示出对癌症治疗非常有希望的结果，例如使处于晚期的白血病患者完全缓解。然而，将 ACT 引入临床治疗不仅需要克服医学方面的挑战，还需要克服技术方面的挑战，例如大量特异性 T 细胞的体外扩增。纳米结构表面代表了一种新的 T 细胞刺激技术，使我们能够精确调整递呈给细胞的激活分子的密度和方向。在这项工作中，我们使用纳米结构表面研究了整合素介导的细胞黏附对 T 细胞激活、增殖和分化的影响，与标准培养物相比，纳米结构表面在纳米尺度上提供了一个定义明确的系统。具体来说，我们合成了一种聚乙二醇（PEG）水凝胶，该水凝胶通过两个纤维连接蛋白衍生肽交联，即环状精氨酸-甘氨酸-天冬氨酸（cRGD）和环状亮氨酸-天冬氨酸-缬氨酸（cLDV），已知这两种肽可激活不同的整合素。此外，水凝胶上还修饰了一个准六边形金纳米粒子（AuNP）阵列，AuNPs 上接枝了激活抗体 CD3，以启动 T 细胞激活。与非功能化的 PEG 水凝胶相比，cLDV 和 cRGD 水凝胶均显示出更高的 T 细胞激活（CD69 表达和 IL-2 分泌）。然而，只有 cRGD 水凝胶在使用小于 150nm 的粒子间距离时，明显支持增殖，产生更高比例的具有记忆（CD4CD45RO）表型的细胞，而不是幼稚（CD4CD45RA）表型的细胞。因此，通过 RGD 序列激活整合素可以增强 T 细胞的增殖。
