药物释放型人造骨架诱导CD8+ T细胞抑制胰腺癌细胞生长和迁移研究

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers with a less than 6% 5-year survival rate. Recently, the role of the immune system in the battle against cancer has garnered a growing attention of scientists. This is particularly boosted by the discovery that CD8+ T cells were able to demolish cancer cells. In our previous research, we demonstrated that drug-eluting electrospun scaffolds could be employed to locally deliver chemotherapy in PDAC for the post-operative management. In this study, we attempt to engage CD8+ T cells using drug-eluting scaffold containing CCL17, a chemokine targeting CCR4 expressed on CD8+ T cells, and facilitate their invasion into cancer tissues. To achieve that, this study is divided into three phases. In the first phase, we will engineer a drug-eluting scaffold containing CCL17. In the second phase, we will confirm that CCL17 was capable of inducing a directional migration of CCR4+CD8+ T cells. In the third phase, we will investigate in vivo if CCL17 released from the scaffold can successfully increase the concentration of CCR4+CD8+ T cells in pancreatic cancer tissues, and inhibit their growth and metastasis. This study will shed new light on how to engineer an immune response to fight cancer.

胰腺导管腺癌（PDAC）是当前恶性程度最高的肿瘤之一，其5年生存率小于6%，积极寻找一种理想有效的治疗方式已成为当务之急。胰腺癌的免疫治疗近年来备受关注，免疫系统特别是CD8+T细胞在杀死癌症细胞中的作用逐渐得到了确认。课题组在前期研究中发现利用药物释放型人造骨架在胰腺癌术后定点释放化疗药物可有效遏制胰腺癌细胞的生长和迁移。在此基础上，本课题将探索如何利用生物材料技术诱导CD8+T细胞进入胰腺癌组织并发挥抑制癌细胞的作用。为实现这个目的，我们分成三步走：1）构建可以释放CCL17趋化因子的人造骨架作为药物投递的媒介；2）确认CCL17可以诱导CCR4+CD8+T细胞的定向迁移；3）在小鼠模型中确认植入的CCL17释放型人造骨架可以诱导CCR4+CD8+T细胞进入胰腺癌组织并抑制癌细胞的生长和迁移。本课题将癌症免疫学与免疫工程学相结合，为传统的生物学治疗胰腺癌提供了一个新的解决方案。

胰腺癌是全球肿瘤相关死亡的主要原因之一。化疗作为目前该疾病的主要治疗手段，通常会引起较为严重的毒副作用。近年来，细胞毒性CD8 + T细胞对癌症细胞的抑制和杀伤作用越来越受到科学家的关注。课题组在前期研究中发现利用药物释放型人造骨架在胰腺癌术后定点释放化疗药物可有效遏制胰腺癌细胞的生长和迁移。 在此基础上，本课题利用生物材料技术诱导CD8+T细胞进入胰腺癌组织并发挥抑制癌细胞的作用，其主要成果包括：1）采用电纺织技术，构建CCL17药物释放型人造骨架；2）检测了药物释放型人造骨架CCL17的释放速率和生物学活性；3）构建胰腺癌干细胞人造骨架，明确人造骨架材料及CCL17本身没有细胞毒性；4）明确CCL17对CCR4+CD8＋ T细胞具有良好的化学趋向性；5）在小鼠模型中确认了植入的CCL17释放型人造骨架可以诱导CCR4+CD8+T细胞进入胰腺癌组织并抑制癌细胞的生长和迁移。本课题将癌症免疫学与免疫工程学相结合，为传统的生物学治疗胰腺癌提供了一个新的解决方案。