Dissecting Stem Cell Intrinsic Signaling Driving Tumor Relapse from Immunotherapy

项目总结 肿瘤是由类似干细胞的群体发起和维持的。然而，我们的身体有一个强大的 免疫监视系统，在癌细胞出现时清除它们。肿瘤起始干细胞是否 (TSCs)被编程为抵抗抗肿瘤免疫和/或它们如何克服免疫屏障 监控仍然鲜为人知。此前，我们设计了一种新型皮肤鳞状细胞癌 (SCC)小鼠模型，可通过基于过继T细胞转移(ACT)的免疫治疗有效靶向， 其中CD8细胞毒性T细胞被设计成识别肿瘤特异性新抗原，然后是 被激活并重新引入体内以攻击肿瘤。在这个模型中，我们成功地演示了 TSCs的一个亚群对抗原特异性T细胞治疗出人意料地无效，并导致肿瘤 旧病复发。由于肿瘤复发是接受ACT治疗的主要临床障碍，了解这些因素 维持免疫逃避干细胞对于限制ACT的复发至关重要。因此，用我的坚强 免疫学背景我特别感兴趣的是这些高度可塑性的干细胞是如何接受特殊提示的 对抗肿瘤免疫产生抵抗力或变得逃避。我们的初步数据显示TSCS 必须依次经历三个阶段，涉及不同的免疫逃避。具体来说，TSCS必须首先， 在最初的肿瘤清除阶段忍受大量的T细胞攻击；然后在静止的同时变得静止 逃避免疫检测，保持较长时间的休眠；最后，按顺序排除正在渗透的T细胞 以解除休眠并产生复发的肿瘤。我们假设特定的信号提示激活不同的 在肿瘤复发的三个阶段中的每一个阶段干细胞中的基因队列并决定着阶段特异性 免疫规避程序。在这一假设的推动下，基于强大的初步数据，我发现Wnt/β- 连环蛋白信号是干细胞功能的基本途径，在这三个肿瘤阶段中的每一个阶段都是至关重要的。 旧病复发。现在，我设计了全面的研究目标，系统地询问干细胞，并寻求 从ACT中筛选Wnt调控基因及其促进肿瘤各阶段复发的机制 治疗。我对剩下的博士后培训的计划是获得更多的技能并发展 研究工具来解决这个有趣的问题，并打开一扇门，以建立独立 学术界。我的长期研究目标是确定新的可用药靶点，这些靶点可能会导致 旨在消除TSCS的下一代免疫疗法。我期待我的独创性 调控肿瘤免疫逃逸的新的Wnt靶点的方法和识别将使我能够建立一个 为未来的独立研究计划奠定坚实的基础。更重要的是，我希望产生的数据 来自我相关但独立的AIMS将揭开新的肿瘤内在靶点的面纱，这些靶点不仅将扩大我们的 肿瘤-免疫相互作用的知识，但也为开发新的策略来增强 目前ACT治疗的有效性和克服这一主要临床障碍。

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.