Childhood high-risk sarcoma derived human satellite (HSAT) and endogenous retroviral (ERV) RNAs in immunosuppression and inflammation

总体中心摘要 本申请描述了创建于2009年的儿科俄亥俄州-纽约约克癌症（Peds-ONC）免疫治疗中心。 对RFA的反应作为儿科免疫疗法发现和开发的第二个病灶 财团（PI-DDN）。为了补充PI-DDN资助的U 54（Maris和Mackall，MPI）， 寻求利用适应性免疫来进一步开发针对新识别抗原的CAR-T细胞，我们提出 利用先天免疫来靶向儿科癌症，避免对常规治疗的抵抗， 进一步实现适应性/混合免疫方法。 我们的目标是（1）识别和克服利用NK和CAR-NK细胞作为癌症治疗的障碍，（2） 破坏对“自身”癌症相关蛋白的耐受性和（3）通过靶向抑制性免疫疗法增强免疫疗法。 骨髓细胞我们将通过四个项目来实现我们的目标，这些项目位于俄亥俄州的两个主要地点 （全国儿童医院）和纽约（纽约医学院），在哥伦布设有分中心（ 俄亥俄州州立大学）和明尼阿波利斯（明尼苏达大学）。除了管理共享之外， 资源（核心A，由蒂莫西·克里普博士和副主任米切尔·开罗博士指导），这些项目是 由全面的基因组学和免疫监测共享资源（核心B，指导 由伊莱恩·马迪斯博士和几位助理主任）。核心B通过状态- 最先进的技术，包括大规模细胞计数，单细胞转录组学，以及一系列其他基因组学 这些方法能够详细表征和跟踪癌细胞免疫原性，肿瘤免疫原性， 微环境和免疫反应。我们还汇集了强大的外部和内部科学 由知名领导人组成的咨询委员会，他们的专业知识涵盖项目和共享资源。的项目 是高度整合和交叉信息的。我们建议，治疗方案，联合收割机的方式将 产生协同作用，在临床前儿科癌症模型中驱动抗肿瘤免疫应答， 低突变负荷的局限性。我们的目标是生成足够的知识体系， 这些数据将为未来临床试验的合理设计提供信息，从而改善癌症儿童的生活。 1

Overall Center Abstract This application describes the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center, created in response to the RFA as a second nidus for the Pediatric Immunotherapy Discovery and Development Consortium (PI-DDN). To complement the funded U54 (Maris and Mackall, MPI) of the PI-DDN that largely seeks to harness adaptive immunity to further develop CAR-T cells against newly identified antigens, we propose to harness innate immunity to target pediatric cancers, to circumvent resistance to conventional therapy, and to further enable adaptive/hybrid immune approaches. Our aims are to (1) Identify and overcome barriers to utilizing NK and CAR-NK cells as cancer therapeutics, (2) break tolerance to “self” cancer-associated proteins and (3) enhance immunotherapies by targeting suppressive myeloid cells. We will accomplish our aims through four projects, based at two major sites based in Ohio (Nationwide Children’s Hospital) and New York (New York Medical College) with subsites in Columbus (The Ohio State University) and Minneapolis (Univeristy of Minnesota). In addition to an Administrative Shared Resource (Core A, directed by Dr. Timothy Cripe and Associate Director Dr. Mitchell Cairo), the projects are scientifically supported by a comprehensive Genomics & Immune Monitoring Shared Resource (Core B, directed by Dr. Elaine Mardis with several subspecialy assistant directors). Core B provides integrated datasets via state- of-the-art technologies including mass cytometry, single cell transcriptomics, and an array of other genomics approaches that enable detailed characterizations and tracking of cancer cell immunogenicity, the tumor immune microenvironment, and immunologic responses. We have also assembled strong external and internal scientific advisory boards of renowned leaders whose expertise spans the projects and shared resources. The projects are highly integrated and cross-informative. We propose that therapeutic regimens that combine modalities will produce synergy that drives anti-tumor immune responses in preclinical pediatric cancer models, overcoming the limitations of low mutational burdens. Our goal is to generate a sufficient body of knowledge with compelling data to inform the rational design of future clinical trials and thereby improve the lives of children with cancer. 1