细胞毒性T细胞
生物
癌细胞
癌症研究
白细胞介素21
CD8型
NKG2D公司
链霉菌
T细胞
白血病
抗原提呈细胞
免疫学
癌症
抗原
免疫系统
体外
生物化学
遗传学
作者
Victoria Marcu-Malina,Sabine Heijhuurs,Marit van Buuren,Linda M Hartkamp,Susanne Strand,Zsolt Sebestyén,Kirsten Scholten,Anton C. Martens,Jürgen Kuball
出处
期刊:Blood
[American Society of Hematology]
日期:2011-07-07
卷期号:118 (1): 50-59
被引量:99
标识
DOI:10.1182/blood-2010-12-325993
摘要
Major limitations of currently investigated αβT cells redirected against cancer by transfer of tumor-specific αβTCR arise from their low affinity, MHC restriction, and risk to mediate self-reactivity after pairing with endogenous α or βTCR chains. Therefore, the ability of a defined γ9δ2TCR to redirect αβT cells selectively against tumor cells was tested and its molecular interaction with a variety of targets investigated. Functional analysis revealed that a γ9δ2TCR efficiently reprograms both CD4(+) and CD8(+) αβT cells against a broad panel of cancer cells while ignoring normal cells, and substantially reduces but does not completely abrogate alloreactivity. γ9δ2TCR-transduced αβT cells reduced colony formation of progenitor cells of primary acute myeloid leukemia blasts and inhibited leukemia growth in a humanized mouse model. Thereby, metabolites of a dysregulated mevalonate pathway are targeted and the additional application of widely used biphosphonates is crucial for in vivo efficacy most likely because of its modulating effect on cytokine secretion of γ9δ2TCR-transduced αβT cells. Expression of NKG2D ligands and F1-ATPase contributed to the activity of γ9δ2TCR-transduced αβT cells but were not mandatory. In summary, γ9δ2 TCRs are an attractive alternative to broadly redirect αβT cells against cancer cells with both an improved efficacy and safety profile compared with currently used αβTCRs.
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