Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains.
Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains.
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使用相同识别域的人类TCR和汽车介导的T细胞活性的比较。
DOI：
10.4049/jimmunol.1700236
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发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Kranz DM
中科院分区：
文献类型：
--
作者：
Harris DT;Hager MV;Smith SN;Cai Q;Stone JD;Kruger P;Lever M;Dushek O;Schmitt TM;Greenberg PD;Kranz DM
免疫性T细胞疗法已经取得了显著的临床反应，特别是在造血系统癌症中。两种类型的受体系统已被用于重定向T细胞的活性，正常的异源二聚体T细胞受体（TCR）或合成的嵌合抗原受体（汽车）。TCR识别肽-HLA复合物，而汽车通常使用识别癌症相关细胞表面抗原的抗体衍生的scFv（单链片段可变）。虽然这两种受体介导不同的效应子功能，但由于它们在亲和力和配体方面的差异，TCR和汽车的灵敏度和信号传导能力的定量比较受到限制。在这里，我们通过使用TCR描述了它们的直接比较，所述TCR可以被格式化为常规αβ异二聚体，或者被格式化为与CD 3 β和CD 28信号传导结构域或仅与CD 3 β连接的scFv构建体。使用两种针对MART 1/HLA-A2或WT 1/HLA-A2的高亲和力TCR（KD值约为50和250 nM），使得MART 1或WT 1肽滴定能够容易地评估抗原密度的影响。尽管汽车的表面表达水平高于TCR，但即使在不存在CD 8共受体的情况下，它们的敏感性也低10至100倍。数学建模表明，较低的CAR敏感性可归因于较低效率的信号传导动力学。此外，在TCR和汽车的高抗原密度下观察到的细胞因子分泌减少表明负调节剂在两种系统中的作用。有趣的是，在高抗原密度下，汽车还介导一些细胞因子（如IL-2和IL-6）的更大最大释放。这些结果对用于过继性T细胞疗法的下一代受体设计具有影响。
Adoptive T cell therapies have achieved significant clinical responses, especially in hematopoietic cancers. Two types of receptor systems have been used to redirect the activity of T cells, normal heterodimeric T-cell receptors (TCRs) or synthetic chimeric antigen receptors (CARs). TCRs recognize peptide-HLA complexes whereas CARs typically use an antibody-derived scFv (single-chain fragments variable) that recognizes cancer-associated cell-surface antigens. While both receptors mediate diverse effector functions, a quantitative comparison of the sensitivity and signaling capacity of TCRs and CARs has been limited due to their differences in affinities and ligands. Here we describe their direct comparison by using TCRs that could be formatted either as conventional αβ heterodimers, or as scFv constructs linked to CD3ζ and CD28 signaling domains or to CD3ζ only. Two high-affinity TCRs (KD values of approximately 50 and 250 nM) against MART1/HLA-A2 or WT1/HLA-A2 were used, allowing MART1 or WT1 peptide titrations to easily assess the impact of antigen density. Although CARs were expressed at higher surface levels than TCRs, they were 10 to 100-fold less sensitive, even in the absence of the CD8 co-receptor. Mathematical modeling demonstrated that lower CAR sensitivity could be attributed to less efficient signaling kinetics. Furthermore, reduced cytokine secretion observed at high antigen density for both TCRs and CARs suggested a role for negative regulators in both systems. Interestingly, at high antigen density, CARs also mediated greater maximal release of some cytokines, such as IL-2 and IL-6. These results have implications for next-generation design of receptors used in adoptive T cell therapies.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
影响因子：
7
作者：
Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
8.8
作者：
Fitzgerald JC;Weiss SL;Maude SL;Barrett DM;Lacey SF;Melenhorst JJ;Shaw P;Berg RA;June CH;Porter DL;Frey NV;Grupp SA;Teachey DT
通讯作者：
Teachey DT
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
16.8
作者：
Dushek O;van der Merwe PA
通讯作者：
van der Merwe PA