SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR-T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target Cells.
SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR-T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target Cells.
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DOI：
10.1021/acs.jproteome.1c00735
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发表时间：
2022-02-04
影响因子：
4.4
通讯作者：
Salomon AR
中科院分区：
文献类型：
--
作者：
Griffith AA;Callahan KP;King NG;Xiao Q;Su X;Salomon AR
嵌合抗原受体（CAR）是一种单次跨膜受体，旨在特异性靶向和消除癌症。虽然汽车证明对B细胞恶性肿瘤高度有效，但促进CAR T细胞活性的细胞内信号传导事件仍然难以捉摸。为了进一步了解CAR T细胞信号传导和CAR靶向细胞的潜在信号传导应答，我们通过液相色谱-串联质谱法（LC-MS/MS）分析了由两种单独的磷酸化富集策略从与SILAC标记的Raji B细胞共培养的第三代CD 19-CAR T细胞捕获的磷酸肽。在这里，我们报告了CD 19-CAR T细胞上调了在经典T细胞受体（TCR）信号传导中也观察到的几个关键磷酸化事件，而Raji B细胞响应于共培养而表现出B细胞受体信号传导相关磷酸化事件的显著减少。我们的数据表明，CD 19-CAR刺激激活独特的CD 19-CAR特异性信号传导途径和经典TCR信号传导的混合物，而Raji B细胞中的整体磷酸化在与CD 19-CAR T细胞缔合后减少。
Chimeric antigen receptor (CAR) is a single-pass transmembrane receptor designed to specifically target and eliminate cancers. While CARs prove highly efficacious against B cell malignancies, the intracellular signaling events which promote CAR T cell activity remain elusive. To gain further insight into both CAR T cell signaling and the potential signaling response of cells targeted by CAR, we analyzed phosphopeptides captured by two separate phopshoenrichment strategies from third generation CD19-CAR T cells cocultured with SILAC labeled Raji B cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we report that CD19-CAR T cells upregulated several key phosphorylation events also observed in canonical T cell receptor (TCR) signaling while Raji B cells exhibited a significant decrease in B cell receptor-signaling related phosphorylation events in response to coculture. Our data suggest that CD19-CAR stimulation activates a mixture of unique CD19-CAR-specific signaling pathways and canonical TCR signaling while global phosphorylation in Raji B cells is reduced after association with the CD19-CAR T cells.
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影响因子：
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作者：
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Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
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Sadelain M
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Su, Xiaolei
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Sadelain M
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Berg, LJ