美国斯隆-凯特林癌症研究所Michel Sadelain、Jorge Mansilla-Soto等研究人员合作开发出HLA非依赖的T细胞受体用于靶向低抗原密度的肿瘤。该项研究成果于2022年1月13日在线发表在《自然—医学》上。

通过T细胞受体（CD3复合物）重新配置来利用与匹配的嵌合抗原受体（CAR）相同的免疫球蛋白重链和轻链，研究人员编辑了人类外周血T细胞中的TRAC位点来参与细胞表面靶标。研究人员证明，这些与HLA无关的T细胞受体（HIT受体）始终提供高抗原敏感性，并介导肿瘤识别，超过了基于CD28的CAR（迄今为止最敏感的设计）所能提供的。研究人员证明，HIT T细胞的功能持久性可以通过CD80和4-1BBL的组成性共表达得到增强。

最后，研究人员在B细胞白血病和急性骨髓性白血病的异种移植小鼠模型中验证了HIT受体所提供的抗原敏感性增加，分别靶向CD19和CD70。总的来说，HIT受体非常适用于靶向低丰度的细胞表面抗原。

据悉，CAR是指导有效免疫反应的抗原受体。与目标抗原低表达相关的肿瘤逃逸正在成为其疗效的一个潜在限制。

附：英文原文

Title: HLA-independent T cell receptors for targeting tumors with low antigen density

Author: Mansilla-Soto, Jorge, Eyquem, Justin, Haubner, Sascha, Hamieh, Mohamad, Feucht, Judith, Paillon, Nomie, Zucchetti, Andrs Ernesto, Li, Zhuoning, Sjstrand, Maria, Lindenbergh, Pieter L., Saetersmoen, Michelle, Dobrin, Anton, Maurin, Mathieu, Iyer, Archana, Garcia Angus, Andreina, Miele, Matthew M., Zhao, Zeguo, Giavridis, Theodoros, van der Stegen, Sjoukje J. C., Tamzalit, Fella, Rivire, Isabelle, Huse, Morgan, Hendrickson, Ronald C., Hivroz, Claire, Sadelain, Michel

Issue&Volume: 2022-01-13

Abstract: Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor–CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance. HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression.

DOI: 10.1038/s41591-021-01621-1

Source: https://www.nature.com/articles/s41591-021-01621-1