Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.
Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.
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DOI：
10.1126/scisignal.abe2606
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发表时间：
2021-08-24
影响因子：
7.3
通讯作者：
Riddell SR
中科院分区：
文献类型：
--
作者：
Salter AI;Rajan A;Kennedy JJ;Ivey RG;Shelby SA;Leung I;Templeton ML;Muhunthan V;Voillet V;Sommermeyer D;Whiteaker JR;Gottardo R;Veatch SL;Paulovich AG;Riddell SR
嵌合抗原受体(CAR)修饰的T细胞疗法在治疗淋巴瘤、白血病和多发性骨髓瘤方面是有效的，在这些肿瘤细胞中，肿瘤细胞具有高含量的靶抗原。然而，要实现患者的持久缓解并将这种疗法推广到实体瘤患者，将需要CAR T细胞来消除靶抗原密度较低的肿瘤。尽管CARS被设计为模拟T细胞受体(TCR)信号，但TCR对抗原的敏感度至少高出100倍。为了设计一种提高抗原敏感性的CAR，我们比较了原代人类T细胞中TCR和CAR信号对ROR1的反应，ROR1是一种与B细胞慢性淋巴细胞白血病相关的跨膜神经营养酪氨酸激酶。磷酸化蛋白质组学分析表明，关键的T细胞信号蛋白，如组成T细胞共受体的CD3δ、CD3ε和CD3γ，以及TCR接头蛋白LAT，在CAR刺激下要么没有磷酸化，要么只有微弱的磷酸化。在淋巴瘤、白血病和乳腺癌的培养和体内模型中，修改CAR序列以更好地结合CD3ε和LAT(具体地说，包含CD3ζ或GRB2结构域的BB/εCARS)可增强T细胞对低密度抗原肿瘤细胞的激活。这些汽车代表了受体设计改变的例子，这些改变是由对T细胞信号的深入询问指导的。
Chimeric antigen receptor (CAR)-modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells have high amounts of target antigen. However, achieving durable remission in patients and extending this therapy to patients with solid tumors will require CAR T cells that can eliminate tumors with a low density of target antigen. Although CARs were designed to mimic T cell receptor (TCR) signaling, TCRs are at least 100-fold more sensitive to antigen. To design a CAR with improved antigen sensitivity, we compared TCR and CAR signaling in primary human T cells in response to ROR1, a transmembrane neurotrophic tyrosine kinase that is associated with B-cell chronic lymphocytic leukemia. Phosphoproteomic analysis revealed that key T cell signaling proteins—such as CD3δ, CD3ε, and CD3γ, which comprise a T cell coreceptor, and the TCR adaptor protein LAT—were either not phosphorylated or were only weakly phosphorylated by CAR stimulation. Modifying the CAR sequence to better engage CD3ε and LAT (specifically, BB/ζ CARs containing CD3ε or GRB2 domains) resulted in enhanced T cell activation against tumor cells with a low density of antigen, in both culture and in vivo models of lymphoma, leukemia, and breast cancer. These CARs represent examples of alterations in receptor design that were guided by in-depth interrogation of T cell signaling.
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影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
影响因子：
16.6
作者：
Helsen CW;Hammill JA;Lau VWC;Mwawasi KA;Afsahi A;Bezverbnaya K;Newhook L;Hayes DL;Aarts C;Bojovic B;Denisova GF;Kwiecien JM;Brain I;Derocher H;Milne K;Nelson BH;Bramson JL
通讯作者：
Bramson JL
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
发表时间：
2018-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Harris DT;Hager MV;Smith SN;Cai Q;Stone JD;Kruger P;Lever M;Dushek O;Schmitt TM;Greenberg PD;Kranz DM
通讯作者：
Kranz DM
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M