德国弗莱堡大学Susana Minguet小组利用CD3多样性优化CAR T细胞。相关论文于2023年11月6日在线发表在《自然—免疫学》杂志上。

研究人员表示，目前美国食品和药物管理局批准的嵌合抗原受体（CAR）T细胞除了具有共刺激结构域外，还具有T细胞受体（TCR）衍生的ζ链作为细胞内激活结构域。TCR复合物的其他链（即CD3δ、CD3ε和CD3γ，而非ζ）在CAR形式中的功能仍不清楚。

研究人员系统地设计了新的CD3 CAR，每种CAR都只含有一个CD3细胞内结构域。研究人员发现，含有CD3δ、CD3ε或CD3γ细胞质尾部的CAR在体内的表现优于传统的ζ CAR T细胞。转录组和蛋白质组分析揭示了激活潜能、新陈代谢和刺激诱导的T细胞功能障碍的差异，从机理上解释了抗肿瘤性能增强的原因。此外，CAR的二聚化提高了它们的整体功能。利用这些CAR作为最小化的合成替代TCR，研究人员发现磷酸酶SHP-1是CD3δ新的相互作用伙伴，它能在CD3δ-ITAM C端酪氨酸磷酸化时与其结合。SHP-1可减弱和抑制激活信号，从而防止衰竭和功能障碍。这些对T细胞活化的新认识可促进合成抗原受体的合理再设计，从而改善癌症免疫疗法。

附：英文原文

Title: Harnessing CD3 diversity to optimize CAR T cells

Author: Velasco Crdenas, Rub M.-H., Brandl, Simon M., Melndez, Ana Valeria, Schlaak, Alexandra Emilia, Buschky, Annabelle, Peters, Timo, Beier, Fabian, Serrels, Bryan, Taromi, Sanaz, Raute, Katrin, Hauri, Simon, Gstaiger, Matthias, Lassmann, Silke, Huppa, Johannes B., Boerries, Melanie, Andrieux, Geoffroy, Bengsch, Bertram, Schamel, Wolfgang W., Minguet, Susana

Issue&Volume: 2023-11-06

Abstract: Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cells harbor the T cell receptor (TCR)-derived ζ chain as an intracellular activation domain in addition to costimulatory domains. The functionality in a CAR format of the other chains of the TCR complex, namely CD3δ, CD3ε and CD3γ, instead of ζ, remains unknown. In the present study, we have systematically engineered new CD3 CARs, each containing only one of the CD3 intracellular domains. We found that CARs containing CD3δ, CD3ε or CD3γ cytoplasmic tails outperformed the conventional ζ CAR T cells in vivo. Transcriptomic and proteomic analysis revealed differences in activation potential, metabolism and stimulation-induced T cell dysfunctionality that mechanistically explain the enhanced anti-tumor performance. Furthermore, dimerization of the CARs improved their overall functionality. Using these CARs as minimalistic and synthetic surrogate TCRs, we have identified the phosphatase SHP-1 as a new interaction partner of CD3δ that binds the CD3δ–ITAM on phosphorylation of its C-terminal tyrosine. SHP-1 attenuates and restrains activation signals and might thus prevent exhaustion and dysfunction. These new insights into T cell activation could promote the rational redesign of synthetic antigen receptors to improve cancer immunotherapy. Minguet and colleagues systematically examine how individual CD3 chains of the TCR–CD3 complex can improve chimeric antigen receptor (CAR) T cell performance.

DOI: 10.1038/s41590-023-01658-z

Source: https://www.nature.com/articles/s41590-023-01658-z