Abstract：
Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.
摘要：
癌症由于免疫原性差而逃避宿主的免疫监视。这里,我们报告了一种免疫抑制剂，称为PTIR1，可作为肿瘤免疫抗性的启动子。PTIR1通过DDX58（RIG-I）的选择性剪接在人类癌症中被选择性诱导，其诱导与癌症患者的不良预后密切相关。通过阻断白细胞的募集，PTIR1促进癌症免疫逃逸和对免疫治疗治疗的肿瘤固有抗性。不像RIG-I,PTIR1能够与UCHL5的C端结合并激活其泛素化功能，从而抑制免疫蛋白酶体活性并限制新抗原加工和呈递，从而阻断T细胞识别和攻击癌症。此外，我们发现腺苷脱氨酶ADAR1在DDX58转录物上诱导A-to-IRNA编辑，从而触发PTIR1的生产。总的来说，我们的数据揭示了PTIR1在肿瘤发生中的免疫抑制作用,并提出ADAR1-PTIR1-UCHL5信号传导是一个潜在的癌症免疫治疗靶点.
