美国贝勒医学院Thomas F. Westbrook小组的一项最新研究表明，在三阴性乳腺癌中剪接体靶向疗法（STT）触发抗病毒免疫反应。相关论文在线发表在2021年1月14日出版的《细胞》杂志上。
研究人员发现错误剪接的RNA通过类似病毒模拟的方式引起对肿瘤细胞的杀伤。在MYC诱导的三阴性乳腺癌中，STT导致的错接mRNA在细胞质中大量积累，其中许多形成双链结构。双链RNA（dsRNA）结合蛋白可识别这些内源dsRNA，从而引起抗病毒信号传导和外源性细胞凋亡。在具有免疫能力的乳腺癌模型中，STT导致肿瘤细胞内在抗病毒信号的传导、下游适应性免疫信号传导和肿瘤细胞死亡。
此外，人乳腺癌中的RNA错误剪接与先天性和适应性免疫相关，特别是在MYC扩增的肿瘤中，这种肿瘤通常具有免疫敏感性。这些发现表明，dsRNA传感途径对癌症中RNA剪接异常敏感，并提出了STT可能通过未知途径来激活抗肿瘤免疫的假说。
据介绍，许多致癌物会破坏RNA剪接，通常导致肿瘤对剪接体靶向疗法敏感。但是，STTs选择性杀死癌症的机制仍然未知。
附：英文原文
Title: Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer
Author: Elizabeth A. Bowling, Jarey H. Wang, Fade Gong, William Wu, Nicholas J. Neill, Ik Sun Kim, Siddhartha Tyagi, Mayra Orellana, Sarah J. Kurley, Rocio Dominguez-Vidaa, Hsiang-Ching Chung, Tiffany Y.-T. Hsu, Julien Dubrulle, Alexander B. Saltzman, Heyuan Li, Jitendra K. Meena, Gino M. Canlas, Srinivas Chamakuri, Swarnima Singh, Lukas M. Simon, Calla M. Olson, Lacey E. Dobrolecki, Michael T. Lewis, Bing Zhang, Ido Golding, Jeffrey M. Rosen, Damian W. Young, Anna Malovannaya, Fabio Stossi, George Miles, Matthew J. Ellis, Lihua Yu, Silvia Buonamici, Charles Y. Lin, Kristen L. Karlin, Xiang H.-F. Zhang, Thomas F. Westbrook
Issue&Volume: 2021-01-14
Abstract: Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivityof tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by whichSTTs selectively kill cancers remain largely unknown. Herein, we discover that mis-splicedRNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driventriple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-splicedmRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteinsrecognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis.In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviralsignaling, downstream adaptive immune signaling, and tumor cell death. Furthermore,RNA mis-splicing in human breast cancers correlates with innate and adaptive immunesignatures, especially in MYC-amplified tumors that are typically immune cold. Thesefindings indicate that dsRNA-sensing pathways respond to global aberrations of RNAsplicing in cancer and provoke the hypothesis that STTs may provide unexplored strategiesto activate anti-tumor immune pathways.
DOI: 10.1016/j.cell.2020.12.031
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31753-0