(PQ3) Modulation of Osteosarcoma Biology by Inflammation and Immunity Defined through a ComparativeApproach

项目摘要 本申请是为了响应NCI挑衅性问题（PQ）倡议而提交的，以解决PQ #3， “肿瘤相关免疫反应的变化如何导致癌症风险，发病率， 还是进步？”本PQ的目的是鼓励研究可变肿瘤的原因- 相关的免疫应答和/或这些变化如何与癌症风险、发病率或进展相关。我们 重点是骨肉瘤，这是一种罕见的疾病，主要影响儿童和青少年。研究区 重要的是要解决骨肉瘤患者在病因学方面的重大未满足的健康需求， 疾病，管理进展的策略，以及指导个性化治疗的方法。我们选择 使用探索性R21机制作为假设检验和假设生成的手段， 通过大规模的测序工作，我们已经产生了一个独特的资源，原发性和转移性 来自患有骨肉瘤的人、狗和小鼠的样本。这项工作包括对生殖系DNA进行测序， 鉴定从头和获得性突变、转录组和甲基化组。为了补充这些主要和 我们已经建立了强大的模型来研究骨肉瘤的进展， 异种移植物以及免疫系统在完全免疫活性小鼠中的作用。我们组建了一个 强大的团队，在肉瘤生物学和治疗，儿科肿瘤学， 流行病学和统计学，兽医学和病理学，动物模型，遗传学和基因组学 工程，炎症，免疫学和免疫治疗，分子生物学，转录，microRNA 网络、系统生物学和生物信息学。该提案包括智力和技术创新 在多物种比较的方法，整合多个人类和动物模型，以及在 将被测试的概念框架。具体来说，我们将研究两个直接相关的问题 PQ：对于具体目标1，我们将研究炎症和免疫之间是否存在相关性， 肿瘤环境中的细胞浸润和肿瘤的生物学行为。这一目标的数据将为我们提供信息， 先天肿瘤性状作为免疫反应的重要驱动因素的情况，使我们能够假设 因果关系假设，以便在未来更大的项目中进行测试。具体目标2旨在确定 骨肉瘤中免疫浸润模式的驱动机制。从这一目标的数据，无论 保守或物种特异性，将证实一个新的和令人兴奋的机制，肿瘤介导的 免疫调节可以用作生物标志物，并且也可以是治疗上易处理的。总的来说， 该项目有可能影响患者的管理和临床试验评估肉瘤的选择 免疫疗法

PROJECT SUMMARY This application is submitted in response to the NCI Provocative Questions (PQ) Initiative to address PQ #3, “How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?” The intent of this PQ is to encourage research to study the causes of variable tumor- associated immune responses and/or how these variations relate to cancer risk, incidence, or progression. Our focus is osteosarcoma, a rare disease that primarily impacts children and adolescents. The research area is important to address significant unmet health needs for osteosarcoma patients with regard to the etiology of the disease, strategies to manage progression, and methods to guide personalized treatments. We chose to use the exploratory R21 mechanism as a means for hypothesis-testing and hypothesis generation from a massive sequencing effort through which we have generated a unique resource of primary and metastatic samples from humans, dogs, and mice with osteosarcoma. The effort includes sequencing of germ line DNA to identify de novo and acquired mutations, transcriptomes and methylomes. To complement these primary and autochthonous samples, we have developed robust models to study the osteosarcoma progression using xenografts as well as the role of the immune system in fully immunocompetent mice. We have assembled a robust team with diverse and comprehensive expertise in sarcoma biology and therapy, pediatric oncology, epidemiology and statistics, veterinary medicine and pathology, animal models, genetics and genomic engineering, inflammation, immunology and immunotherapy, molecular biology, transcription, microRNA networks, and systems biology and bioinformatics. The proposal includes intellectual and technical innovations in the multi-species comparative approach integrating multiple human and animal models, as well as in the conceptual frameworks that will be tested. Specifically we will investigate two issues that are directly pertinent to the PQ: For specific aim 1, we will investigate if there are correlations between inflammatory and immune cell infiltrates in the tumor environment and the biological behavior of the tumors. Data from this aim will inform the case for innate tumor traits as significant drivers of the immune response, allowing us to postulate a causality hypothesis for test it in a future larger project. Specific aim 2 is designed to determine the mechanisms that drive patterning of immune infiltrates in osteosarcoma. Data from this aim, whether conserved or species-specific, will confirm a new and exciting mechanism of tumor-mediated immunomodulation that could be used as a biomarker, and that also could be therapeutically tractable. Overall, the project has the potential to impact patient management and selection for clinical trials evaluating sarcoma immunotherapy.