Chronic viral mimicry induction following p53 loss promotes immune evasion [STIC RNASeq]. Chronic viral mimicry induction following p53 loss promotes immune evasion [STIC RNASeq]

Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception. Overall design: STIC RNASeq *** Submitter declares raw data will be uploaded to a repository that can be controlled for the confidentiality of the patients. ***

可改变DNA和/或组蛋白修饰的表观遗传疗法，能够促进免疫原性重复序列元件的转录，后者可通过"病毒模拟"应答清除癌细胞。矛盾的是，包括经典肿瘤抑制蛋白功能失活在内的癌症起始事件，同样会促进重复序列元件的转录。目前对于重复序列元件转录在癌症起始中的作用，以及肿瘤发生过程中癌细胞如何规避致命性病毒模拟应答的机制，仍知之甚少。
在本研究中，我们对患者来源的输卵管癌前病变以及上皮性卵巢癌的同基因小鼠模型进行了表征，以探索p53肿瘤抑制蛋白缺失后肿瘤发生的早期事件。我们发现，p53缺失会破坏组成型异染色质，从而允许可激活病毒模拟应答的免疫原性重复序列元件进行转录。尽管急性病毒模拟激活会降低细胞存活适应性，但p53缺失后的慢性病毒模拟激活会促进表观遗传重编程，增强细胞对胞质核酸的耐受性，并降低细胞免疫原性，以此作为一种促存活的适应机制。我们将这一选择过程命名为"病毒模拟预适应（viral mimicry conditioning）"，该过程可被逆转录酶抑制剂3TC部分阻断，从而延缓自发性肿瘤发生。
综上，本研究结果表明，p53缺失后的病毒模拟预适应会选择出免疫原性降低的细胞，以促进癌症起始阶段的免疫逃逸。在癌症起始阶段阻断病毒模拟预适应，或可成为早期癌症干预的药理学靶点。
实验设计概述：STIC RNA测序
*** 提交者声明：原始数据将上传至可保障患者隐私安全的受控存储库 ***