美国斯坦福大学医学院K. Christopher Garcia团队取得最新进展。他们发现可通过增强磷酸酶募集（RIPR）来抑制免疫受体。相关论文于2020年10月21日发表于国际顶尖学术期刊《自然》。

他们提出了一种衰减细胞表面受体信号的替代方法，称为通过RIPR抑制受体。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与混杂的细胞表面磷酸酶CD45进行顺式连接，从而导致受体靶标上酪氨酸残基的直接胞内去磷酸化。例如，他们发现通过程序性细胞死亡1受体（PD-1）进行的补体信号传导会导致T细胞活化的残基抑制，但不会被配体-拮抗剂抗体抑制。他们设计了一个PD-1分子，并将其表示为RIPR-PD1，它诱导PD-1与CD45的交联并抑制补体和配体激活的信号传导。

与抗PD1抗体的配体阻断相比，RIPR-PD1表现出对检查点阻断的抑制作用增强，并且在小鼠肿瘤模型中相对于抗PD1抗体具有更高的治疗功效。他们还表明，RIPR策略可扩展到其他包含激活或抑制性ITIM，ITSM或ITAM的免疫受体靶标；例如，使用SIRPα-CD45RIPR分子抑制巨噬细胞SIRPα“不要吃我”信号，可增强抗体依赖性细胞吞噬作用，而不仅仅是SIRPα阻断作用。RIPR代表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。

据悉，拮抗细胞外受体-配体相互作用的抗体被用作许多疾病的治疗剂，以抑制细胞表面受体的信号传导。但是，这种方法不能直接防止细胞内信号传导，例如通过配体结合后的补体或持续信号传导。

附：英文原文

Title: Immune receptor inhibition through enforced phosphatase recruitment

Author: Ricardo A. Fernandes, Leon Su, Yoko Nishiga, Junming Ren, Aladdin M. Bhuiyan, Ning Cheng, Calvin J. Kuo, Lora K. Picton, Shozo Ohtsuki, Robbie G. Majzner, Skyler P. Rietberg, Crystal L. Mackall, Qian Yin, Lestat R. Ali, Xinbo Yang, Christina S. Savvides, Julien Sage, Michael Dougan, K. Christopher Garcia

Issue&Volume: 2020-10-21

Abstract: Antibodies that antagonize extracellular receptor–ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors1. 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 CD452,3, 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.

DOI: 10.1038/s41586-020-2851-2

Source: https://www.nature.com/articles/s41586-020-2851-2