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靶向TdT的T细胞可选择性杀死白血病淋巴细胞
2021-12-11 10:43

挪威奥斯陆大学Johanna Olweus小组发现靶向TdT的T细胞可选择性杀死白血病淋巴细胞。2021年12月6日,《自然—生物技术》杂志在线发表了这项成果。

研究人员表示,与嵌合抗原受体不同,T细胞受体(TCR)可以识别人类白细胞抗原(HLA)分子上呈递的细胞内目标。

研究人员证明了表达特异性TCR的T细胞,在HLA-A*02:01的背景下呈递的细胞内淋巴细胞特异性酶末端脱氧核苷酸转移酶(TdT),在体外和三个传播性B-ALL的小鼠模型中特异性地消除T和B细胞来源的原发性急性淋巴细胞白血病(ALL)细胞。相比之下,这种治疗方法在体外和人源化小鼠体内保留了正常的外周T细胞和B细胞重现,以及正常的骨髓细胞。

TdT是一个有吸引力的癌症靶点,因为它在80-94%的B-和T-ALL中高度均匀地表达,但在正常淋巴分化过程中只短暂表达,限制了TdT特异性T细胞的靶向毒性。以TdT为靶点的TCR修饰T细胞可能是一种有希望的B-ALL和T-ALL免疫疗法,并可以保留正常淋巴细胞。

附:英文原文

Title: T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

Author: Ali, Muhammad, Giannakopoulou, Eirini, Li, Yingqian, Lehander, Madeleine, Virding Culleton, Stina, Yang, Weiwen, Knetter, Cathrine, Odabasi, Mete Can, Bollineni, Ravi Chand, Yang, Xinbo, Foldvari, Zsofia, Bschen, Maxi-Lu, Taraldsrud, Eli, Strnen, Erlend, Toebes, Mireille, Hillen, Amy, Mazzi, Stefania, de Ru, Arnoud H., Janssen, George M. C., Kolstad, Arne, Tjnnfjord, Geir Erland, Lie, Benedicte A., Griffioen, Marieke, Lehmann, Sren, Osnes, Liv Toril, Buechner, Jochen, Garcia, K. Christopher, Schumacher, Ton N., van Veelen, Peter A., Leisegang, Matthias, Jacobsen, Sten Eirik W., Woll, Petter, Olweus, Johanna

Issue&Volume: 2021-12-06

Abstract: Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that Tcells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific Tcells. TCR-modified Tcells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

DOI: 10.1038/s41587-021-01089-x

Source: https://www.nature.com/articles/s41587-021-01089-x

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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