Immune receptor inhibition through enforced phosphatase recruitment.
Immune receptor inhibition through enforced phosphatase recruitment.
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DOI：
10.1038/s41586-020-2851-2
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Garcia KC
中科院分区：
文献类型：
--
作者：
Fernandes RA;Su L;Nishiga Y;Ren J;Bhuiyan AM;Cheng N;Kuo CJ;Picton LK;Ohtsuki S;Majzner RG;Rietberg SP;Mackall CL;Yin Q;Ali LR;Yang X;Savvides CS;Sage J;Dougan M;Garcia KC
拮抗细胞外受体-配体相互作用的抗体用作许多疾病的治疗剂以抑制细胞表面受体的信号传导。然而，这种方法不直接阻止细胞内信号传导，例如通过配体接合后的紧张或持续信号传导。在这里，我们提出了一种减弱细胞表面受体信号传导的替代方法，称为磷酸酶募集受体抑制（RIPR）。这种方法迫使含有ITAM、ITIM或ITSM酪氨酸磷酸化基序的细胞表面受体顺式连接到混杂的细胞表面磷酸酶CD 45，这导致受体靶标上的酪氨酸残基的直接细胞内去磷酸化。例如，我们发现程序性细胞死亡-1受体（PD-1）的紧张性信号传导导致T细胞活化的残余抑制，但不被配体拮抗剂抗体抑制。我们设计了一种PD-1分子，我们将其命名为RIPR-PD 1，它诱导PD-1与CD 45的交联，并抑制紧张性和配体激活的信号传导。在小鼠肿瘤模型中，与抗PD 1抗体的配体阻断相比，RIPR-PD 1表现出对检查点阻断的抑制增强，并且与抗PD 1相比，治疗功效增加。我们还表明，RIPR策略扩展到其他免疫受体靶点，包含激活或抑制ITIM，ITSM或ITAM基序;例如，用SIRPα-CD 45 RIPR分子抑制巨噬细胞SIRPα“不要吃我”信号，增强抗体依赖性细胞吞噬作用，超过单独SIRPα阻断作用。RIPR代表了一种通过激酶激活的细胞表面受体直接减弱信号传导的一般策略。
Antibodies that antagonize extracellular receptor–ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors. However, this approach does not directly prevent intracellular signalling, such as through tonic or sustained signalling after ligand engagement. Here we present an alternative approach for attenuating cell-surface receptor signalling, termed receptor inhibition by phosphatase recruitment (RIPR). This approach compels cis-ligation of cell-surface receptors containing ITAM, ITIM or ITSM tyrosine phosphorylation motifs to the promiscuous cell-surface phosphatase CD45, which results in the direct intracellular dephosphorylation of tyrosine residues on the receptor target. As an example, we found that tonic signalling by the programmed cell death-1 receptor (PD-1) results in residual suppression of T cell activation, but is not inhibited by ligand-antagonist antibodies. We engineered a PD-1 molecule, which we denote RIPR-PD1, that induces cross-linking of PD-1 to CD45 and inhibits both tonic and ligand-activated signalling. RIPR-PD1 demonstrated enhanced inhibition of checkpoint blockade compared with ligand blocking by anti-PD1 antibodies, and increased therapeutic efficacy over anti-PD1 in mouse tumour models. We also show that the RIPR strategy extends to other immune-receptor targets that contain activating or inhibitory ITIM, ITSM or ITAM motifs; for example, inhibition of the macrophage SIRPα ‘don’t eat me’ signal with a SIRPα–CD45 RIPR molecule potentiates antibody-dependent cellular phagocytosis beyond that of SIRPα blockade alone. RIPR represents a general strategy for direct attenuation of signalling by kinase-activated cell-surface receptors.
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影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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