CORE 2: Outreach Core

摘要 检查点阻断抗体和过继T细胞转移取得了令人兴奋的临床突破 改变了癌症免疫治疗领域，展示了利用免疫系统 消灭癌细胞。然而，根本性的挑战和问题依然存在。显著的临床反应 只在一小部分患者和癌症类型中观察到，目前尚不清楚 肿瘤的性质决定了临床反应，也决定了在以下情况下应采取什么策略 目前的免疫疗法是无效的。最终解决这些临床挑战并设计 癌症治疗可以预见的有效，我们必须加深对相互作用的基本理解 在分子、细胞和系统水平上，肿瘤和免疫系统之间的关系。CSBC研究 MSKCC癌症系统免疫学中心将带来系统生物学的工具来研究 癌症-免疫系统在疾病发展的多个阶段相互作用以回答以下中心问题 癌症免疫学和为设计新的免疫治疗干预措施提供信息。 我们围绕三个中心科学项目组织了我们的研究中心，这些项目检查癌症免疫 疾病发展不同阶段的相互作用：癌症起始和早期肿瘤形成(项目I)； 已确诊和进展中的肿瘤(项目II)；潜伏性疾病和转移(项目III)。在项目I中，我们 将新的表观基因组学技术和创新的单细胞分析与最先进的系统相结合 破译功能性肿瘤潜在分子和表观遗传程序的生物学方法- 肿瘤早期发生中的特异性T细胞分化。我们将进一步阐明突变中的动力学 肿瘤抗原分布、间质和免疫细胞群决定了这些状态、模型和测试 在小鼠和人类肿瘤中，不同的T细胞状态决定了对免疫检查点阻断的敏感性。在……里面 项目二，我们将使用功能、流式细胞仪、 群体rna-seq和液滴rna测序与癌症、免疫和免疫的生态学模型 基质细胞群体研究肿瘤生态系统对免疫治疗干扰的反应 已确诊的肿瘤。在项目III中，我们将研究先天免疫系统控制的进化动力学 转移性疾病，癌症免疫学研究的新领域。我们将调查异质性 潜在癌细胞逃避免疫的能力，我们将使用定量方法，包括活的 细胞成像，模拟潜伏的肿瘤细胞逃避先天免疫控制和潜伏周期的动力学 细胞增殖和NK细胞的潜在编辑。共享资源核心将提供最先进的 单细胞液滴测序技术及单细胞RNA序列数据的计算分析 SEQ)。这个共享的资源核心将负责液滴测序技术的开发和设计 并将与所有三个科学项目互动。 我们的研究中心还将在当地开展创新的外展和培训活动， 在国家和全球各级传播癌症系统免疫学的研究成果并培训年轻人 这一新兴领域的科学家。

SUMMARY Exciting clinical breakthroughs with checkpoint blockade antibodies and adoptive T cell transfers have transformed the field of cancer immunotherapy, demonstrating the power of harnessing the immune system to eliminate cancer cells. However, fundamental challenges and questions remain. Significant clinical responses have only been observed in a subset of patients and cancer types, and it is currently not known what biological properties of tumors determine clinical responses, nor what strategies to adopt in clinical contexts where current immunotherapies are ineffective. To ultimately address these clinical challenges and to design predictably effective cancer treatments, we must deepen our fundamental understanding of interactions between tumors and the immune system at the molecular, cellular, and systems levels. The CSBC Research Center for Cancer Systems Immunology at MSKCC will bring the tools of systems biology to investigate cancer-immune system interactions at multiple stages of disease progression to answer central questions in cancer immunology and inform the design of novel immunotherapeutic interventions. We have organized our Research Center around three central scientific projects that examine cancer-immune interactions at distinct stages of disease progression: cancer initiation and early tumorigenesis (Project I); established and progressing tumors (Project II); latent disease and metastasis in (Project III). In Project I, we will combine new epigenomics technologies and innovative single-cell analyses with state-of-the-art systems biology approaches to decipher the underlying molecular and epigenetic programs of dysfunctional tumor- specific T cell differentiation in early tumorigenesis. We will further elucidate how dynamics in the mutational tumor antigen landscape and stromal and immune cell populations determine such states and model and test in mouse and human tumors how distinct T cell states determine sensitivity to immune checkpoint blockade. In Project II, we will use quantitative analysis of cell types and cell states by functional, flow cytometric, population RNA-seq and droplet RNA sequencing together with ecological models of cancer, immune, and stromal cell populations to study the response of the tumor ecosystem to immunotherapeutic perturbations in established tumors. In Project III, we will examine the evolutionary dynamics of innate immune system control of metastatic disease, a new area of investigation in cancer immunology. We will investigate the heterogeneity of latent cancer cells in their capacity for immune evasion, and we will use quantitative methods, including live cell imaging, to model latent tumor cell evasion of innate immune control and the dynamics of cycles of latent cell proliferation and potential editing by NK cells. A Shared Resource Core will provide state-of-the-art single-cell droplet sequencing technology and computational analysis of single-cell RNA-seq data (scRNA- seq). This Shared Resource Core will be tasked with droplet sequencing technology development and design of novel algorithmic approaches and will interact with all three scientific Projects. Our Research Center will also carry out an innovative program of outreach and training activities at the local, national, and global levels to disseminate research findings in cancer systems immunology and to train young scientists in this emerging field.