Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy
Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy
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DOI：
10.1016/j.celrep.2019.05.041
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发表时间：
2019-06-11
期刊：
影响因子：
8.8
通讯作者：
Malissen, Bernard
中科院分区：
文献类型：
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作者：
Celis-Gutierrez, Javier;Blattmann, Peter;Malissen, Bernard
解读TCR信号是如何被共抑制受体调节的具有基础和临床意义。使用定量相互作用组学，我们定义了PD-1和BTLA共抑制信号体在初级效应T细胞和T细胞-抗原呈递细胞界面的组成和动力学。我们还解决了目前关于SHP-1和SHP-2蛋白酪氨酸磷酸酶在介导PD-1共抑制中的作用的争议。PD-1主要招募SHP-2，但当不存在时，它招募SHP-1并保持功能。相比之下，BTLA主要招募SHP-1，并在较小程度上招募SHP-2。通过分别分析PD-1-SHP-1和PD-1-SHP-2复合物，我们发现两者都同样抑制TCR和CD 28信号通路。因此，我们的研究说明了如何通过原代T细胞中的定量相互作用组学比较共抑制受体信号传导，揭示了它们的冗余程度，并为基于无可争议的作用模式设计癌症免疫治疗中的阻断抗体组合提供了理论基础。
Deciphering how TCR signals are modulated by coinhibitory receptors is of fundamental and clinical interest. Using quantitative interactomics, we define the composition and dynamics of the PD-1 and BTLA coinhibitory signalosomes in primary effector T cells and at the T cell-antigen-presenting cell interface. We also solve the existing controversy regarding the role of the SHP-1 and SHP-2 protein-tyrosine phosphatases in mediating PD-1 coinhibition. PD-1 predominantly recruits SHP-2, but when absent, it recruits SHP-1 and remains functional. In contrast, BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2. By separately analyzing the PD-1-SHP-1 and PD-1-SHP-2 complexes, we show that both dampen the TCR and CD28 signaling pathways equally. Therefore, our study illustrates how comparison of coinhibitory receptor signaling via quantitative interactomics in primary T cells unveils their extent of redundancy and provides a rationale for designing combinations of blocking antibodies in cancer immunotherapy on the basis of undisputed modes of action.