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

项目总结 本申请是对NCI挑衅性问题(PQ)倡议的回应，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？“这个PQ的目的是鼓励研究各种肿瘤的原因- 相关的免疫反应和/或这些变异如何与癌症风险、发病率或进展相关。我们的 焦点是骨肉瘤，这是一种主要影响儿童和青少年的罕见疾病。研究领域是 重要的是要解决骨肉瘤患者在病因方面尚未得到满足的重大健康需求 疾病，管理进展的策略，以及指导个性化治疗的方法。我们选择了 使用探索性R21机制作为假设测试和假设生成的方法 大量的测序工作，通过这些工作，我们产生了一个独特的原发和转移资源 来自人类、狗和患有骨肉瘤的小鼠的样本。这项工作包括对生殖系DNA进行测序，以 确定从头开始和获得性突变、转录本和甲基组。为了补充这些主要和 ，我们已经开发出稳健的模型来研究骨肉瘤的进展 异种移植以及免疫系统在完全具有免疫能力的小鼠中的作用。我们已经组建了一支 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 工程学、炎症、免疫学和免疫疗法、分子生物学、转录、微核糖核酸 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。 在整合多种人和动物模型的多物种比较方法中，以及在 将接受测试的概念性框架。具体地说，我们将调查两个直接相关的问题 对于PQ：对于特定的目标1，我们将调查炎症和免疫之间是否存在关联 肿瘤细胞侵袭肿瘤的环境和肿瘤的生物学行为。来自该目标的数据将向您提供 与生俱来的肿瘤特征是免疫反应的重要驱动因素，这使得我们能够假设 在未来更大的项目中检验它的因果关系假说。具体目标2旨在确定 驱动骨肉瘤免疫浸润物图案化的机制。来自这个目标的数据，无论是 保守或物种特异性，将证实一种新的、令人兴奋的肿瘤介导机制 免疫调节可以用作生物标记物，而且在治疗上也是容易处理的。总的来说， 该项目有可能影响患者的管理和选择评估肉瘤的临床试验 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.