Dissecting Stem Cell Intrinsic Signaling Driving Tumor Relapse from Immunotherapy

剖析干细胞内在信号传导导致免疫治疗肿瘤复发

• 批准号: 10200232
• 负责人: Yuxuan Phoenix Miao
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200232
• 关键词: Academia; Adopted; Animals; Automobile Driving; Binding; CD8-Positive T-Lymphocytes; CD80 gene; Cancerous; Cell Death; Cell physiology; Cells; ChIP-seq; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Cytotoxic T-Lymphocytes; Data; Detection; Development; Discipline; Exclusion; Flow Cytometry; Foundations; Future; Genes; Genomics; Human; Image; Immune; Immune Evasion; Immune Targeting; Immunologic Surveillance; Immunology; Immunotherapy; In Vitro; Knowledge; Lead; Link; Malignant Neoplasms; Mechanics; Modeling; Molecular; Monitor; Natural regeneration; Nature; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phenotype; Plant Roots; Population; Primary Neoplasm; Proteins; Refractory; Regulatory Element; Relapse; Reporter; Research; Resistance development; Role; Signal Transduction; Smad Proteins; Solid; System; T cell response; T cell therapy; T-Lymphocyte; Testing; Tissues; Transforming Growth Factor beta; Tumor Escape; Tumor Immunity; Tumor stage; Tumor-infiltrating immune cells; Up-Regulation; WNT Signaling Pathway; antigen-specific T cells; autocrine; base; beta catenin; cancer immunotherapy; cancer therapy; cohort; cytotoxic CD8 T cells; design; engineered T cells; experience; fascinate; genome editing; immune resistance; improved; in vivo; in vivo Model; inhibitor/antagonist; interest; mouse model; neoantigens; neoplastic cell; new therapeutic target; next generation; novel; originality; post-doctoral training; preservation; programs; skills; skin squamous cell carcinoma; stem cells; stem-like cell; tool; transcription factor; tumor

PROJECT SUMMARY Tumors are initiated and maintained by a stem cell-like population. However, our bodies have a powerful immune surveillance system to clear out cancerous cells as they emerge. Whether tumor-initiating stem cells (tSCs) are programmed to resist anti-tumor immunity and/or how they overcome the barrier of immune surveillance remains poorly understood. Previously, we have designed a novel skin squamous cell carcinoma (SCC) mouse model that can be effectively targeted by adoptive T cell transfer (ACT) based immunotherapy, in which the CD8+ cytotoxic T cells are engineered to recognize a tumor-specific neoantigen, then are activated and reintroduced to the body to attack tumor. In this model, we have successfully demonstrated that a subset of tSCs are surprisingly refractory to the antigen-specific T cell treatment, and cause the tumor to relapse. Since tumor relapse is a major clinical obstacle for patients receiving ACT, understanding the factors that sustain immune evasive SCs is paramount for limiting relapse in ACT. Therefore, with my strong background in immunology, I'm especially interested in how these highly plastic stem cells receive special cues to develop resistance or become evasive to the anti-tumor immunity. Our preliminary data shows that tSCs must sequentially undergo three stages involving distinct immune evasive. Specifically, the tSCs must firstly, endure massive T cell attack during the initial primary tumor clearance stage; then become quiescent while still evade immune detection to maintain a long period of dormancy; finally, exclude the infiltrating T cells in order to exit dormancy and generate relapsed tumors. We hypothesize that specific signaling cue activates different cohort of genes in stem cells during each of the three stage of tumor relapse and dictates stage-specific immune evasive program. Driven by this hypothesis and built on strong preliminary data, I found that Wnt/β- Catenin signaling, an essential pathway for stem cell functions is critical in each of these three stages of tumor relapse. Now I designed comprehensive research aims to systematically interrogate the stem cells and sought to identify Wnt-regulated genes and their mechanisms promoting each stage of tumor relapse from ACT treatment. My plan for the remainder of my postdoctoral training is to acquire additional skills and develop research tools to tackle this fascinating question, and to open a door for establishing independence in academia. My long-term research objective is to identify new druggable targets that could potentially lead to next generation of immunotherapy that is designed to eliminate the tSCs. I expect the originality of my approaches and identification of novel Wnt targets regulating tumor immune evasion will allow me to build a solid foundation for a future independent research program. More importantly, I expect that the data generated from my related but independent aims will unveil new tumor-intrinsic targets that will not only expand our knowledge of tumor-immune interactions, but also pave the way to develop new strategies to enhance the efficacy of current ACT treatments and surmount this major clinical obstacle.

项目摘要 肿瘤由干细胞样群体启动和维持。但是，我们的身体有强大的 免疫监视系统以清除癌细胞出现。肿瘤发射干细胞是否 （TSC）编程以抵抗抗肿瘤免疫学和/或它们如何克服免疫学障碍 监视仍然很少理解。以前，我们设计了一种新型的皮肤鳞状细胞癌 （SCC）可以通过自适应T细胞转移（ACT）免疫疗法有效靶向的小鼠模型， CD8+细胞毒性T细胞设计以识别肿瘤特异性新抗原，然后是 被激活并重新引入人体以攻击肿瘤。在此模型中，我们成功证明了 TSC的一个子集令人惊讶地对抗原特异性T细胞处理难治性，并导致肿瘤 由于肿瘤缓解是接受ACT患者的主要临床障碍，因此了解这些因素 维持免疫发射SC是限制ACT中继的至关重要的。因此，我坚强 免疫学背景，我对这些高度塑料干细胞如何获得特殊提示特别感兴趣 产生抗性或对抗肿瘤免疫力产生反应。我们的初步数据表明TSCS 必须顺序进行三个阶段，涉及不同的免疫反射。具体而言，TSC必须首先 在最初的原发性肿瘤清除阶段耐用大规模T细胞攻击；然后静止不动 逃避免疫检测以保持长时间的休眠；最后，按顺序排除浸润的T细胞 退出休眠并产生继电器肿瘤。我们假设特定的信号提示激活了不同的 在肿瘤缓解的三个阶段中的每个阶段，干细胞中的基因队列并决定了阶段特异性 免疫回避计划。在这一假设的驱动下，并建立在强大的初步数据上，我发现Wnt/β- catenin信号传导，在这三个阶段的肿瘤中的每个阶段中，干细胞功能的必要途径至关重要 复发。现在，我设计了全面的研究旨在系统地询问干细胞并出现 鉴定受Wnt调节的基因及其机制促进肿瘤缓解的每个阶段 治疗。我对博士后培训的其余计划的计划是获得其他技能并发展 解决这个有趣的问题的研究工具，并为建立独立性打开一扇门 学术界。我的长期研究目标是确定有可能导致的新型吸毒目标 旨在消除TSC的下一代免疫疗法。我期望我的独创性 调节肿瘤免疫避免的新型WNT目标的方法和识别将使我能够建立一个 未来独立研究计划的坚实基础。更重要的是，我希望数据生成 从我相关但独立的目标中，将揭示新的肿瘤内在目标，不仅会扩大我们的 了解肿瘤免疫相互作用，但也为开发新策略的方式铺平了道路 当前ACT治疗的功效并克服这一主要临床障碍。