Investigating the interplay between senescence and T cell immunity

项目摘要/摘要 候选人：我一直以来的兴趣之一是了解一个成功的抗肿瘤T细胞的介体 细胞反应。在这份申请中，我提出了一系列的研究，其中我结合了我的研究生学习 T细胞生物学背景和我的导师Scott Lowe博士的实验室在体内癌症方面的专业知识 建模和肿瘤抑制。我在纪念斯隆·凯特琳癌症中心洛威实验室的研究 (MSKCC)专注于衰老，这是传统抗癌疗法的常见后果， 影响T细胞的功能。在这里，我勾勒出一个过渡到独立的计划，这将使我 为了：(I)完成一系列导致发现的实验，我将能够继续作为一个 独立调查员；(2)获得一套专门知识，并进一步发展一条研究路线，使我 从我现在和过去的导师那里学习和(Iii)培养领导实验室所需的一系列专业技能。 研究：癌细胞中的细胞衰老是应激诱导的程序，导致细胞周期稳定 阻止和抑制过多的细胞因子的分泌，这些细胞因子可以影响包括免疫在内的其他细胞的行为 细胞。衰老已被证明在不同的疾病中具有免疫刺激或免疫抑制的作用 上下文。细胞衰老是抗肿瘤治疗的常见结果，但确切的机制是通过 衰老对适应性抗肿瘤免疫反应的影响在很大程度上尚不清楚。这个项目的目标是 利用我开发的新的癌症模型，研究衰老对T细胞的功能影响。 在目标1中，我将探索不同的衰老驱动因素如何导致T细胞渗透或排斥T细胞 肿瘤微环境。在目标2中，我将探索一种免疫刺激形式的衰老如何影响 衰老和非衰老癌细胞所特有的T细胞的功能。这些研究将告诉我们 衰老如何影响抗肿瘤T细胞反应以及如何合理设计更好的抗癌药物 诱导衰老的方法。 环境：MSKCC为我实现培训和研究目标提供了一个理想的环境， 并成功过渡到学术机构的独立教员职位。我的导师洛博士是 癌症生物学的世界领先者，在肿瘤抑制程序、小鼠模型和 功能遗传学。此外，我还组建了一个由三位知名科学家组成的顾问委员会， 相关和互补的专业知识以及对指导的坚定承诺(佩尔博士、鲁登斯基博士和罗森博士)， 世卫组织将通过提供有价值的研究和职业指导来支持我向独立的过渡。同舟共济 借助MSKCC的协作环境和广泛的资源，该支持网络创建了 成功完成拟议的研究和职业发展计划的最佳条件。

PROJECT SUMMARY/ABSTRACT CANDIDATE: One of my long-standing interests is to understand the mediators of a successful antitumoral T cell response. In this application, I am proposing a series of studies where I combine my graduate study background in T cell biology with the expertise of the laboratory of my mentor Dr. Scott Lowe in in vivo cancer modeling and tumor suppression. My research in the Lowe lab at Memorial Sloan Kettering Cancer Center (MSKCC) has focused on how senescence, a common consequence of conventional anticancer therapies, affects the function of T cells. Here I am delineating a plan for transitioning to independence that will allow me to: (i) complete a set of experiments that are leading to discoveries I will be able to continue exploring as an independent investigator; (ii) Acquire a set of expertise and further develop a research line that will separate me from my present and past mentors and (iii) develop a series of professional skills needed for leading a lab. RESEARCH: Cellular senescence in cancer cells is a stress-induced program that results in stable cell cycle arrest and in secretion of a plethora of cytokines that can affect the behavior of other cells, including immune cells. Senescence has been shown to have an immunostimulatory or immunosuppressive role in different contexts. Cellular senescence is a common outcome of antitumoral therapies, yet the precise mechanisms by which senescence alters adaptive anti-tumor immune responses remain largely unexplored. This project aims at studying the functional consequences of senescence on T cells, utilizing novel model of cancer I have developed. In Aim 1, I will explore how different drivers of senescence can lead to a T cell-infiltrated or a T cell-excluded tumor microenvironment. In Aim 2 I will explore how an immunostimulatory form of senescence affects the functionality of T cells that are specific for senescent and non-senescent cancer cells. These studies will inform on how senescence can affect an antitumoral T cell response and on how to rationally design better anticancer senescence-inducing approaches. ENVIRONMENT: MSKCC provides an ideal environment for me to accomplish my training and research goals, and successfully transition to an independent faculty position at an academic institution. My mentor Dr. Lowe is a world leader in cancer biology, with a particular expertise on tumor suppressor programs, mouse models, and functional genetics. In addition, I have assembled an advisory committee of three established scientists with relevant and complementary expertise and strong commitment to mentoring (Drs. Pe’er, Rudensky, and Rosen), who will support my transition to independence by providing valuable research and career guidance. Together with the collaborative environment and broad spectrum of resources at MSKCC, this support network creates optimal conditions for the successful completion of the proposed research and career development plans.