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

整体中心摘要 此应用程序描述了儿科俄亥俄-纽约癌症免疫治疗中心(PEDS-ONC)，创建于 作为儿科免疫疗法发现和发展的第二个病灶--RFA的反应 联盟(PI-DDN)。为了补充PI-DDN资助的U54(Maris和Mackall，MPI)，这在很大程度上 寻求利用获得性免疫来进一步开发针对新发现的抗原的CAR-T细胞，我们建议 利用针对儿科癌症的先天免疫，绕过对传统疗法的抵抗，并 进一步启用适应性/混合免疫方法。 我们的目标是(1)识别和克服将NK细胞和CAR-NK细胞用作癌症治疗的障碍，(2) 打破对“自身”癌症相关蛋白的耐受性和(3)通过靶向抑制来加强免疫治疗 髓系细胞。我们将通过俄亥俄州两个主要地点的四个项目来实现我们的目标 (全国儿童医院)和纽约(纽约医学院)在哥伦布设有分支机构(The 俄亥俄州立大学)和明尼阿波利斯(明尼苏达大学)。除了管理共享 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，定向)提供科学支持 由伊莱恩·马迪斯博士和几个分专业的助理导演)。核心B通过以下方式提供集成数据集： 最先进的技术，包括质量细胞术、单细胞转录组学和一系列其他基因组学 能够详细描述和跟踪癌细胞免疫原性、肿瘤免疫的方法 微环境和免疫反应。我们还集结了强大的外部和内部科学技术 由知名领导人组成的顾问委员会，他们的专业知识涵盖了项目和共享资源。这些项目 是高度集成的，具有交叉信息性。我们建议，结合多种方式的治疗方案将 在临床前儿科癌症模型中产生协同作用，驱动抗肿瘤免疫反应，克服 低突变负担的局限性。我们的目标是用令人信服的方式生成足够多的知识 数据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