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无效CAR-近端信号减弱抗原敏感性
作者:小柯机器人 发布时间:2020/7/8 13:38:33

奥地利维也纳医科大学Johannes B. Huppa和德国维尔茨堡大学医院Michael Hudecek研究组合作取得最新进展。他们揭示无效的嵌合抗原受体(CAR)-近端信号减弱了抗原敏感性。该研究于2020年7月6日发表于《自然—免疫学》。

他们通过定量、单分子、活细胞成像分析了CAR介导的抗原识别,发现CAR T细胞对抗原的敏感性比T细胞抗原受体介导的名义肽(主要组织相容性复合物)降低了约1000倍。尽管CAR在免疫突触中的抗原结合性能优于T细胞抗原受体,但由于酪氨酸蛋白激酶ZAP-70不能有效地募集至连接的CAR,且其伴随的活化和随后的释放减弱,近端信号显著减弱。他们的研究揭示了目前最先进的CAR设计的信号缺陷,这些缺陷限制了CAR T细胞疗法靶向抗原表达降低的肿瘤的功效。

据介绍,具有优化的抗癌性能的CAR的合理设计,要求对CAR如何与肿瘤抗原结合,以及抗原结合如何触发激活进行详细了解。

附:英文原文

Title: Inefficient CAR-proximal signaling blunts antigen sensitivity

Author: Venugopal Gudipati, Julian Rydzek, Iago Doel-Perez, Vasco Dos Reis Gonalves, Lydia Scharf, Sebastian Knigsberger, Elisabeth Lobner, Renate Kunert, Hermann Einsele, Hannes Stockinger, Michael Hudecek, Johannes B. Huppa

Issue&Volume: 2020-07-06

Abstract: Rational design of chimeric antigen receptors (CARs) with optimized anticancer performance mandates detailed knowledge of how CARs engage tumor antigens and how antigen engagement triggers activation. We analyzed CAR-mediated antigen recognition via quantitative, single-molecule, live-cell imaging and found the sensitivity of CAR T cells toward antigen approximately 1,000-times reduced as compared to T cell antigen-receptor-mediated recognition of nominal peptide–major histocompatibility complexes. While CARs outperformed T cell antigen receptors with regard to antigen binding within the immunological synapse, proximal signaling was significantly attenuated due to inefficient recruitment of the tyrosine-protein kinase ZAP-70 to ligated CARs and its reduced concomitant activation and subsequent release. Our study exposes signaling deficiencies of state-of-the-art CAR designs, which presently limit the efficacy of CAR T cell therapies to target tumors with diminished antigen expression.

DOI: 10.1038/s41590-020-0719-0

Source: https://www.nature.com/articles/s41590-020-0719-0

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex