Investigating the interplay between senescence and T cell immunity

项目总结/摘要 候选人：我长期以来的兴趣之一是了解成功的抗肿瘤T细胞介导剂。 细胞反应。在这个应用程序中，我提出了一系列的研究，我联合收割机我的研究生学习 我有T细胞生物学的背景，我的导师Scott Lowe博士在体内癌症实验室的专业知识 建模和肿瘤抑制。我在纪念斯隆凯特琳癌症中心的劳实验室的研究 （MSKCC）专注于如何衰老，一个常见的结果，传统的抗癌疗法， 影响T细胞的功能。我在这里描绘了一个过渡到独立的计划， （一）完成一系列实验，这些实验将导致我能够作为一名科学家继续探索的发现。 独立调查员;（二）获得一套专业知识，并进一步发展一个研究线，将我分开 从我现在和过去的导师和（iii）开发一系列的专业技能需要领导一个实验室。 研究：癌细胞的细胞衰老是一种应激诱导的程序，导致稳定的细胞周期 抑制和分泌过多的细胞因子，这些细胞因子可以影响其他细胞的行为，包括免疫细胞， 细胞衰老已被证明具有免疫刺激或免疫抑制作用，在不同的免疫系统中， contexts.细胞衰老是抗肿瘤治疗的常见结果，然而， 衰老改变了适应性抗肿瘤免疫应答，这在很大程度上仍未被探索。该项目旨在 研究衰老对T细胞的功能影响，利用我开发的新癌症模型。 在目标1中，我将探讨不同的衰老驱动因素如何导致T细胞浸润或T细胞排斥 肿瘤微环境在目标2中，我将探索免疫刺激形式的衰老如何影响免疫系统。 在某些实施方案中，所述方法包括检测对衰老和非衰老癌细胞特异的T细胞的功能性。这些研究将提供信息， 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， 衰老诱导方法。 环境：MSKCC为我提供了一个理想的环境，以实现我的培训和研究目标， 并成功过渡到学术机构的独立教师职位。我的导师洛博士 癌症生物学领域的世界领导者，在肿瘤抑制程序、小鼠模型和 功能遗传学此外，我还召集了一个由三位知名科学家组成的咨询委员会， 相关和互补的专业知识和对指导的坚定承诺（Pe'er，Rudensky和罗森博士）， 他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。一起 利用微软科学、技术和文化中心的协作环境和广泛的资源，这个支持网络 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.