约翰霍普金斯大学的医学科学家表示，他们已经开发出一种具有治疗癌症潜力的人工淋巴结, according to a new study in mice and human cells. 新形成的淋巴结——一个充满免疫系统成分的囊——被植入皮肤下, 它被设计成一个学习中心和刺激器，教会免疫系统t细胞识别和杀死癌细胞.

Details of the experiments are published recently online and in the June 6 issue of Advanced Materials.

Lymph nodes — tiny glands throughout the body, mainly in the neck, armpits and groin — are part of the immune systems of mammals, including mice and people. 它们的数量以数百个为单位，这样身体某个部位的免疫细胞就不必跑很远就能提醒免疫系统即将到来的危险.

“They are a landing spot where T-cells, the immune system’s fighting cells, lay dormant, waiting to be activated to fight infections or other abnormal cells,” says Natalie Livingston, Ph.D., 该研究的第一作者，目前是马萨诸塞州总医院的博士后研究员. “Because cancers can trick T-cells into staying dormant, 人工淋巴结被设计用来通知和激活沿着淋巴结注射的t细胞.”

To create the artificial lymph node, the scientists used hyaluronic acid, 一种保湿物质，通常用于化妆品和乳液中，自然存在于人体的皮肤和关节中.

Because of its properties, 透明质酸通常用于生物可降解材料，如伤口愈合贴片，用于植入或应用于身体. 在这些特性中，透明质酸可以通过细胞表面受体与t细胞连接.

Johns Hopkins scientists led by Jonathan Schneck, M.D., Ph.D., published research in 2019 showing that hyaluronic acid boosts T-cell activation.

For the current study, the Johns Hopkins team used hyaluronic acid as the scaffolding, or base, for their new lymph node, 并加入MHC(主要组织相容性复合体)或HLA(人类组织相容性抗原)分子, which rev up T-cells and other immune system components. Then, 他们还添加了癌细胞常见的分子和抗原来“教导”t细胞寻找什么.

“By adding different antibodies to the artificial lymph node, 我们就有能力控制t细胞被激活来寻找什么,” says Livingston.

The resulting artificial lymph node is about 150 microns in size, about twice the width of a human hair. 它足够小，可以留在皮肤下，又足够大，可以避免被血液冲走.

“与CAR-T等其他细胞疗法相比，这种方法的一个优势是制造步骤更少,” says Schneck, who is a professor of pathology, 约翰霍普金斯大学医学院的医学和肿瘤学教授, director of the Johns Hopkins Center for Translational Immunoengineering, and a member of the Institute for Cell Engineering, Kimmel Cancer Center and Institute for NanoBioTechnology.

Current cell-based therapies require extracting T-cells from a patient, 在体外操纵它们来识别一种特定类型的癌症, and injecting them back into the patient. “In our approach, we inject T-cells along with an artificial lymph node, t细胞被体内的人工淋巴结引导和教育. Then, the T-cells can travel anywhere to destroy cancer cells,” says Schneck, who led the research team, along with Hai-Quan Mao, Ph.D., director of Johns Hopkins’ NanoBioTechnology Institute.

Livingston, Schneck和研究小组在植入黑色素瘤或结肠癌的老鼠身上测试了人工淋巴结. Six days after the tumors were implanted, the mice received injections of the artificial lymph node and T-cells.

约翰霍普金斯大学的研究小组将这些小鼠与单独接受人工淋巴结的小鼠进行了比较, 一种是单独接受t细胞治疗(未被人工淋巴结激活)，另一种是t细胞与抗pd -1免疫治疗药物联合接受治疗.

Nine days later, 患有黑色素瘤和结肠癌的老鼠接受了人工淋巴结的组合, t细胞和抗pd -1药物的存活率最高(7只小鼠中有3只在33天时仍然存活)。, compared with other groups that only lived to about 26 days. This group of mice also had the slowest cancer growth rate. 与其他组相比，他们的癌症扩大一倍需要5到10天的时间.

科学家们还发现，人工淋巴结吸引了其他免疫细胞的涌入，并作为一个“免疫活性生态位”，帮助进一步刺激免疫系统. 当t细胞与人工淋巴结一起注射到小鼠体内时, T-cell numbers grew as much as nine times more plentiful.

利文斯顿说，人工淋巴结疗法不同于癌症疫苗, which typically activates a dendritic cell, an immune system component that teaches T-cells what to search for. People with cancer often develop malfunctioning dendritic cells, 人工淋巴结跳过树突细胞直接激活t细胞.

The research team 计划进行更多的实验室研究，向淋巴结添加更多的免疫信号分子，并招募更多的宿主免疫细胞到人工淋巴结环境中.

“我们融合了材料科学和免疫学的学科，创造了一种潜在的疗法，形成了自己的免疫学社区——一种活的药物,” says Schneck.

研究人员已经申请了一项涉及他们研究中描述的技术的专利.

研究经费由美国国立卫生研究院(R01EB029341)提供, R21CA185819, P41EB028239, T32AI007417), the National Science Foundation, the Ruth L. 科施斯坦博士前国家个人研究服务奖(F31CA275271), 约翰霍普金斯纳米生物技术研究所的国立卫生研究院癌症纳米技术培训中心, the National Science Foundation Graduate Research Fellowship, the ARCS Foundation, the Siebel Foundation, 加拿大自然科学与工程研究委员会研究生奖学金-博士奖.

约翰·霍普金斯大学的其他研究人员约翰·希基也参与了这项研究, Hajin Sim, Sebastian Salathe, Joseph Choy, Jiayuan Kong, Aliyah Silver, Jessica Stelzel, Mary Omotoso, Shuyi Li, Worarat Chaisawangwong, Sayantika Roy, Emily Ariail, Mara Lanis, Pratibha Pradeep, Joan Glick Bieler, Savannah Est Witte, Elissa Leonard, Joshua Doloff and Jamie Spangler.

DOI: 10.1002/adma.202310043