美国拉霍亚免疫学研究所Sonia Sharma研究小组在研究中取得进展。他们发现肿瘤抑制性蛋白激酶DAPK3通过STING –IFN-β通路诱导肿瘤固有免疫。相关论文于2021年3月25日发表于国际学术期刊《自然-免疫学》杂志。

通过对1,001个肿瘤抑制基因的功能丧失筛选，研究人员发现与死亡相关蛋白激酶3（DAPK3）是先前未知的抗肿瘤免疫促进因子，其通过胞质DNA感知干扰素基因刺激因子（STING）通路完成免疫逃逸。DAPK3表达或激酶活性的丧失会破坏STING的激活和干扰素（IFN）-β刺激基因的诱导。产生IFN-β肿瘤细胞中DAPK3的缺乏促进了CD103⁺CD8α⁺树突状细胞和细胞毒性淋巴细胞的快速生长并减弱其浸润，从而降低了癌细胞对化学免疫疗法的反应。

从机制上讲，DAPK3介导了STING的翻译后修饰。在未刺激的细胞中，DAPK3抑制了STING K48的多泛素化和蛋白酶体介导的降解。cGAMP刺激后，DAPK3是STING K63多泛素化和STING-TANK结合激酶1相互作用所必需的。利用系统的磷酸蛋白质组学，研究人员发现E3连接酶LMO7上存在DAPK3的特异性磷酸位点，这对LMO7-STING相互作用和STING K63的多泛素化至关重要。因此，DAPK3是STING激活所必需的激酶，可诱导肿瘤固有的先天免疫和肿瘤免疫监视。

据介绍，逃避宿主免疫是癌症的标志。但是，尚不完全清楚致癌突变导致免疫逃逸的机制。

附：英文原文

Title: The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING–IFN-β pathway

Author: Mariko Takahashi, Chan-Wang J. Lio, Anaamika Campeau, Martin Steger, Ferhat Ay, Matthias Mann, David J. Gonzalez, Mohit Jain, Sonia Sharma

Issue&Volume: 2021-03-25

Abstract: Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING–TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7–STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

DOI: 10.1038/s41590-021-00896-3

Source: https://www.nature.com/articles/s41590-021-00896-3