Epigenetic activation of the interferon response to sensitize cancers to immune therapy

 描述(申请人提供)：癌症是美国第二常见的死亡原因，近四分之一的死亡是由癌症引起的。激活宿主免疫系统的治疗方法已经显示出对各种实体肿瘤的巨大希望，患者表现出强烈而持久的反应。然而，只有不到一半的患者对这些免疫疗法有反应。我们已经证明，使用DNA甲基转移酶抑制剂(DNMTis)的表观遗传疗法可以通过激活包括内源性逆转录病毒(ERV)在内的双链RNA来增强来自肿瘤的免疫信号，并使肿瘤对免疫治疗敏感。这项建议的指导阶段的目标是进一步表征ERV的表观遗传调节，并确定DNMTi诱导的肿瘤信号传递给宿主免疫系统的确切机制。在K99阶段，我将1)使用全基因组测序来绘制ERV的表观遗传修饰图谱；2)确定哪些表观遗传修饰药物激活ERV，以及3)表征表观遗传对免疫治疗的敏化所需的细胞液传感器和细胞因子。在K99阶段生物信息学和免疫学培训的基础上，R00阶段的目标是扩大基因组分析，以研究可能有助于DNMTi诱导的免疫反应的其他dsRNA。此外，我将研究RNA编辑的作用，它是细胞对病毒RNA的反应的核心，在 这种免疫反应。总体而言，这些研究将表征表观遗传学在先天免疫反应中的作用，并确定表观遗传学对免疫治疗增敏的机制(S)。这位候选人凯瑟琳·恰皮内利博士长期以来一直对癌症的表观遗传学变化感兴趣。她的独立学术实验室的主要重点将是癌症免疫信号的表观遗传调控。这项K99/R00建议旨在补充Chiappinelli博士之前的研究，并为她提供生物信息学和免疫学方面的额外科学培训，使她能够成功地成为一名独立的研究人员。此外，该提案还包括一个详细的职业发展计划和一个咨询委员会，该委员会将协助奇亚皮内利博士完成向独立调查员的过渡。她的顾问委员会成员将为她提供免疫学(Drew Pardoll，Cynthia Zahnow)和生物信息学(Gordon Mills，Ting Wang)方面的科学培训，以及在她过渡到独立的过程中提供指导(Stephen Baylin，Luis Garza)。这项K99/R00计划将为Chiappinelli博士提供必要的培训，以扩大她博士后工作的成果，并开始她自己独立而成功的研究实验室。

 DESCRIPTION (provided by applicant): Cancer is the second most common cause of mortality in the United States, causing nearly one out of four deaths. Therapies that activate the host immune system have shown tremendous promise for a wide variety of solid tumors, with patients exhibiting vigorous and durable responses. However, fewer than half of patients respond to these immune therapies. We have shown that epigenetic therapy using DNA methyltransferase inhibitors (DNMTis) can "boost" immune signaling from tumors, through activation of double-stranded RNA including endogenous retroviruses (ERVs), and sensitize tumors to immune therapy. The goals of the mentored phase of this proposal are to further characterize ERV epigenetic regulation and determine the exact mechanism of DNMTi-induced tumor signaling to the host immune system. During the K99 phase, I will 1) use whole-genome sequencing to map epigenetic modifications at ERVs; 2) determine which epigenetic modifying drugs activate ERVs, and 3) characterize cytosolic sensors and cytokines necessary for epigenetic sensitization to immune therapy. Building on the bioinformatics and immunology training from the K99 phase, the goal of the R00 phase is to expand the genomic analysis to investigate other dsRNAs that may contribute to the DNMTi-induced immune response. In addition, I will examine the role of RNA editing, central to the cellular response to viral RNA, in this immune response. Overall, these studies will characterize the role of epigenetics in the innate immune response and determine the mechanism(s) for epigenetic sensitization to immune therapy. The candidate, Dr. Katherine Chiappinelli, has a longstanding interest in epigenetic changes in cancer. The main focus of her independent academic laboratory will be epigenetic regulation of immune signaling in cancer. This K99/R00 proposal is designed to complement Dr. Chiappinelli's previous research and provide her with additional scientific training in bioinformatics and immunology to allow her to succeed as an independent investigator. In addition, this proposal includes a detailed career development plan and an advisory committee that will assist Dr. Chiappinelli through the transition to becoming an independent investigator. Members of her advisory committee will provide her with scientific training in immunology (Drew Pardoll, Cynthia Zahnow) and bioinformatics (Gordon Mills, Ting Wang) as well as guidance as she transitions to independence (Stephen Baylin, Luis Garza). This K99/R00 proposal will provide Dr. Chiappinelli with the training needed to extend the findings from her postdoctoral work and begin her own independent and successful research laboratory.