Dynamic Analysis of Tumor and Microenvironment in Patients Undergoing Immunotherapy

项目总结/摘要 利用免疫系统对抗癌症已被证明是非常有效的，但大多数患者 免疫治疗没有反应。我们对决定反应的因素的理解 免疫治疗仍然很差。癌细胞的免疫识别和破坏发生在免疫系统的水平。 肿瘤微环境（TME），但人类TME一直难以研究，由于缺乏合适的 临床前模型，获取足够的患者肿瘤组织的挑战，以及缺乏分析工具， 研究癌症和免疫系统之间复杂的相互作用。在这份提案中，我们将直接 研究免疫治疗随时间推移在患者TME中产生的变化， 在滤泡性淋巴瘤原位接种（ISV）的两项试验中采用连续多部位肿瘤活检方法。我们 利用单细胞基因组学和多参数组织学平台的技术进步， 有限的样本，以及生物信息学的进步，使我们能够提取重要的信息， 从大型复杂数据集中，目标是在治疗前确定关键的肿瘤-免疫相互作用， 免疫反应的演变与治疗。我们将重点讨论T细胞表型和克隆型 肿瘤细胞对ISV的反应是否会增强 抗肿瘤免疫的产生（Aim 2）和TME中细胞之间的相互作用（Aim 3）。这 全面的方法将产生关键的见解成功的免疫治疗的决定因素。 这项工作将由Tanaya Shree，MD PhD，肿瘤学系研究员， 斯坦福大学医学院。Shree博士在康奈尔大学/洛克菲勒大学完成了双MD/PhD课程 大学/斯隆-凯特琳，她发现肿瘤相关的巨噬细胞有助于小鼠乳腺癌 癌症在化疗中存活下来，抑制关键的巨噬细胞功能可以改善化疗 功效在斯坦福大学，Shree博士继续研究癌症和免疫系统， 癌症患者发起的免疫治疗试验，研究了淋巴瘤幸存者的免疫健康，并建立了 在免疫学和研究免疫治疗机制的高维测定方面的专业知识。 博士Shree将由医学博士罗纳德利维和医学博士Hanlee Ji指导这项工作。两人都是医学科学家 他在癌症免疫治疗和基因组学领域做出了重大贡献， 指导了许多成功的独立研究人员。此外，一个杰出的顾问委员会， 由Crystal Mackall博士，Garry Nolan博士和Ash Alizadeh博士组成，将指导她的研究和职业生涯 发展Shree博士的培训计划侧重于高级免疫学的教学和实践培训， 生物信息学和生物统计学，以补充她在生物医学研究方面的丰富技能和经验。

PROJECT SUMMARY / ABSTRACT Harnessing the immune system to fight cancer has proven to be remarkably effective, but most patients who are treated with immunotherapy do not respond. Our understanding of what determines the response to immunotherapy remains poor. Immune recognition and destruction of cancer cells occurs at the level of the tumor microenvironment (TME), but the human TME has been difficult to study due to a lack of suitable preclinical models, the challenges in acquiring adequate patient tumor tissues, and a lack of analytic tools to study the complex interplay between cancer and the immune system. In this proposal, we will directly investigate the changes immunotherapy produces in the TME of patients over time by utilizing samples from a serial multi-site tumor biopsy approach in two trials of in situ vaccination (ISV) in follicular lymphoma. we are leveraging technological advances in single cell genomics and multiparameter histology platforms to study limited samples in great depth as well as bioinformatics advances that allow us to extract important information from large complex datasets with a goal of identifying the key tumor-immune interactions before treatment and the evolution of immune responses with treatment. We will focus on how T-cell phenotypes and clonotypes change after ISV and relate to tumor responses (Aim 1), on whether tumor cell responses to ISV may enhance the generation of anti-tumor immunity (Aim 2), and on interactions between cells in the TME (Aim 3). This comprehensive approach will yield critical insights into the determinants of successful immunotherapy. This work will be undertaken by Tanaya Shree, MD PhD, a fellow in the Department of Oncology at the Stanford University School of Medicine. Dr. Shree completed a dual MD/PhD program at Cornell/ Rockefeller University/ Sloan-Kettering where she discovered that tumor-associated macrophages helped murine breast cancer survive chemotherapy and that dampening critical macrophage functions could improve chemotherapy efficacy. At Stanford, Dr. Shree continues to investigate cancer and the immune system, having developed two investigator-initiated immunotherapy trials, studied the immune health of lymphoma survivors, and established expertise in immunology and high-dimensional assays for studying mechanisms of immunotherapy. Dr. Shree will be mentored in this work by Ronald Levy, MD, and Hanlee Ji, MD. Both are physician-scientists who have made significant contributions to the fields of cancer immunotherapy and genomics and have mentored numerous successful independent researchers. In addition, a distinguished committee of advisors, consisting of Drs. Crystal Mackall, Garry Nolan, and Ash Alizadeh, will guide her research and career development. Dr. Shree’s training plan focuses on didactic and practical training in advanced immunology, bioinformatics, and biostatistics to complement her substantial skills and experience in biomedical research.