Deciphering the System-Wide Immune Response to Head and Neck Cancer

项目总结 头颈部鳞状细胞癌(HNSCC)是世界上第六大常见癌症，影响到 到每年美国境内的4.5万人，5年存活率为57%。免疫检查点 抑制剂(ICIS)使癌症治疗发生了革命性的变化，在一些国家产生了戏剧性的抗肿瘤反应 HNSCC患者；然而，只有大约20%的患者显示出任何生存益处，其中什么预测尚不清楚。 回应。ICIS被认为主要通过重新激活耗尽的细胞毒性CD8+T细胞来发挥作用 (CD8s)存在于实体瘤的肿瘤微环境中。然而，最近的研究表明， 肿瘤微环境(外周免疫系统)外的各种CD4+T细胞群可能发挥作用 在进行抗肿瘤免疫反应中的关键作用。鉴于越来越多的证据表明免疫细胞 CD8对于抗肿瘤免疫是重要的，识别和表征这些细胞是至关重要的，以便 了解它们在HNSCC肿瘤发生和ICI治疗中的作用，目前尚不清楚。这 凯尔·琼斯博士提出的建议旨在显著提高我们对癌症免疫学的理解 在HNSCC肿瘤的背景下，最终目标是改进现有的ICI疗法并开发新的 治疗策略。在多学科指导团队的帮助下，他将使用一种新颖的系统 实现以下目标的生物学方法：(目标1)量化HNSCC肿瘤对 并确定这些变化是否在肿瘤、血液和区域淋巴中保守 (AIM 2)确定ICI atezolizumab如何改变肿瘤内和外周免疫状态 HNSCC患者以及这些变化是否与肿瘤的治疗反应有关。这些目标将定义 HNSCC肿瘤如何在单细胞和系统中改变患者免疫系统的组成和功能 水平以及识别/表征有助于下列抗肿瘤免疫的特定免疫细胞 ICI疗法。琼斯博士将使用高通量的单细胞方法，如质量细胞术，多路离子 HNSCC患者标本的BEAM成像和单细胞RNAseq以及已建立的分析管道 分别于ICI治疗前和治疗后测得。这一方法的创新，允许同时研究所有 免疫细胞，包括CD4+和CD8+亚群，将揭示任何单个免疫细胞的变化 种群会影响整体免疫状态。这对于发现额外的免疫细胞也是很重要的。 ICI治疗后与HNSCC抗肿瘤免疫相关的人群和生物标志物。琼斯博士的 长期的职业目标是成为以下领域的专家、领导者和独立翻译科学家 头颈部癌症免疫学和免疫疗法。通过这个K23奖项，他将获得额外的 实验免疫学、单细胞分析方法、计算机编程、高级 统计方法，以及职业发展，他需要成功实现这一目标。

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and affects up to 45,000 people annually within the United States, with a 5-year survival rate of 57%. Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, resulting in dramatic anti-tumor responses in some HNSCC patients; however, only about 20% show any survival benefit, and of these it is not clear what predicts response. ICIs have been thought to work primarily through reactivation of exhausted cytotoxic CD8+ T cells (CD8s) residing within the tumor microenvironment of solid tumors. Recent work, however, indicates that various CD4+ T cell populations outside the tumor microenvironment (peripheral immune system) likely play critical roles in carrying out anti-tumor immune responses. Given increasing evidence that immune cells other than CD8s are important for anti-tumor immunity, it is critical to identify and characterize these cells in order to understand their roles during HNSCC tumorigenesis and ICI therapy, which are currently unknown. This proposal by Dr. Kyle Jones, DDS, PhD seeks to significantly advance our understanding of cancer immunology in the context of HNSCC tumors, with the ultimate goal of improving existing ICI therapies and developing new treatment strategies. With the assistance of a multi-disciplinary mentoring team, he will use a novel systems biology approach to accomplish the following Aims: (AIM 1) Quantify the effects that HNSCC tumors have on systemic immunity and determine if these changes are conserved across tumor, blood, and regional lymph nodes; (AIM 2) Determine how the ICI atezolizumab alters the intratumoral and peripheral immune states of HNSCC patients and if these changes are associated with tumor response to therapy. These Aims will define how HNSCC tumors alter the composition and function of patients' immune systems at single cell and systems levels as well as identify/characterize the specific immune cells that contribute to anti-tumor immunity following ICI therapy. Dr. Jones will use high throughput single-cell methods such as mass cytometry, multiplexed ion beam imaging, and single-cell RNAseq along with established analytic pipelines on HNSCC patient specimens obtained before and after ICI therapy. The innovation of this approach, which permits simultaneous study of all immune cells, including CD4+ and CD8+ subsets, will reveal how changes in any individual immune cell population affects the overall immune state. It will also be important for the discovery of additional immune cell populations and biomarkers associated with HNSCC anti-tumor immunity following ICI therapy. Dr. Jones's long-term career goal is to become an expert, leader, and independent translational scientist in the fields of head and neck cancer immunology and immunotherapy. Through this K23 award, he will obtain the additional training in experimental immunology, single cell analysis methods, computer programming, advanced statistical methods, and career development he needs to successfully achieve this goal.