卫材肿瘤新欢可杀死三阴性乳腺癌

触发抗病毒免疫可杀死三阴性乳腺癌

　　许多致癌损伤可破坏核糖核酸（RNA）剪接，通常可引起肿瘤对剪接体靶向治疗高度敏感。其中，卫材肿瘤旗下美国H3生物制药口服小分子剪接体调节剂H3B-8800已被尝试用于治疗剪接体突变的骨髓增生异常综合征、急性粒细胞白血病、慢性粒单核细胞白血病。不过，剪接体靶向治疗如何选择性杀死肿瘤的具体机制尚不明确。

　　2021年1月14日，全球自然科学三大旗舰期刊之一美国《细胞》正刊在线发表美国贝勒医学院、卫材肿瘤旗下美国H3生物制药的研究报告，发现被错误剪接的RNA可模仿病毒而触发抗病毒免疫反应杀死三阴性乳腺癌。

　　对于原癌基因MYC高表达的三阴性乳腺癌，剪接体靶向治疗可引起被错误剪接的信使RNA广泛聚集于细胞质，其中许多形成双链结构。双链RNA结合蛋白可识别这些内源性双链RNA，从而触发抗病毒信号传导和外源性细胞凋亡。

　　对于具有免疫能力的乳腺癌模型，剪接体靶向治疗可引起肿瘤细胞先天性抗病毒信号传导、下游获得性免疫信号传导和肿瘤细胞死亡。此外，人类乳腺癌RNA错误剪接与先天性和获得性免疫特征相关，尤其对于MYC高表达肿瘤，此类肿瘤通常为免疫惰性，对免疫治疗反应冷淡。

　　因此，该研究结果表明，剪接体靶向治疗可模仿病毒触发抗病毒先天性免疫反应和下游获得性免疫，继而杀死三阴性乳腺癌，这将为激活抗肿瘤免疫提供新的治疗策略。

　　对此，美国《细胞》旗下《免疫》发表加拿大多伦多大学玛格丽特公主癌症中心的评论：剪接体靶向治疗可诱导双链RNA反应。

Cell. 2021 Jan 14. Online ahead of print.

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.

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-Vidana, 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.

Baylor College of Medicine, Houston, TX, USA; H3Biomedicine, Cambridge, MA, USA.

HIGHLIGHTS

  • Spliceosome-targeted therapies (STTs) induce widespread mis-spliced mRNA in cancer

  • Mis-spliced, intron-retained mRNAs are an unexplored source of endogenous dsRNA

  • STTs trigger antiviral signaling and extrinsic apoptosis in TNBCs via dsRNA sensors

  • RNA mis-splicing in human breast cancers correlates with immune signatures

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

KEYWORDS: RNA splicing in cancer; triple-negative breast cancer; spliceosome-targeted therapies; viral mimicry; antiviral immunity; anti-cancer immunity; MYC; double-stranded RNA; oncogenic stress

DOI: 10.1016/j.cell.2020.12.031

Immunity. 2021 Jan 12;54(1):11-13.

Spliceosome-Targeted Therapies Induce dsRNA Responses.

Charles A. Ishak, Helen Loo Yau, Daniel D. De Carvalho.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; University of Toronto, Toronto, Canada.

In a recent issue of Cell, Bowling et al. describe a mechanism by which spliceosome-targeted therapies result in intron-containing transcripts that form double-stranded RNAs (dsRNAs), thereby activating tumor antiviral signaling (viral mimicry) and downstream adaptive immunity.

DOI: 10.1016/j.immuni.2020.12.012

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