美国德州儿童医院和休斯顿卫理公会医院Maksim Mamonkin团队的一项最新研究表明，工程化的现成治疗性T细胞可抵抗宿主免疫排斥。这一研究成果发表在2020年7月13日出版的《自然-生物技术》上。

在本研究中，研究人员设计了一种受体，该受体可造成宿主激活T细胞和自然杀伤（NK）细胞的缺失，从而防止异体T细胞排斥。该同种免疫防御受体（ADR）选择性识别4-1BB，这是一种被活化淋巴细胞暂时上调的细胞表面受体。表达ADR的T细胞通过在体外和体内靶向同种反应性淋巴细胞来抵抗细胞排斥，同时保留了静息淋巴细胞。

嵌合抗原受体和ADR共表达的细胞在小鼠体内持续存在，在患有造血或实体瘤的两种小鼠模型中，其可以维持同种异体T细胞持续性消除肿瘤。这种方法能够产生抗排斥的“现成的”同种异体T细胞，从而在具有免疫反应的受试者中产生长期治疗益处。

研究人员表示，工程化的T细胞是治疗各种恶性肿瘤的有效方法，但是当前的方法依赖于自身T细胞，自身T细胞产生困难且昂贵。要开发不会被受体免疫系统排斥的有效同种异体T细胞，需要消除T细胞和NK细胞的反应，这可以通过各种机制消除异源细胞。

附：英文原文

Title: Engineered off-the-shelf therapeutic T cells resist host immune rejection

Author: Feiyan Mo, Norihiro Watanabe, Mary K. McKenna, M. John Hicks, Madhuwanti Srinivasan, Diogo Gomes-Silva, Erden Atilla, Tyler Smith, Pinar Ataca Atilla, Royce Ma, David Quach, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin

Issue&Volume: 2020-07-13

Abstract: Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop potent allogeneic T cells that are not rejected by the recipient’s immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK cells, preventing rejection of allogeneic T cells. Our alloimmune defense receptor (ADR) selectively recognizes 4-1BB, a cell surface receptor temporarily upregulated by activated lymphocytes. ADR-expressing T cells resist cellular rejection by targeting alloreactive lymphocytes in vitro and in vivo, while sparing resting lymphocytes. Cells co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers. This approach enables generation of rejection-resistant, ‘off-the-shelf’, allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.

DOI: 10.1038/s41587-020-0601-5

Source: https://www.nature.com/articles/s41587-020-0601-5