Investigating the interplay between senescence and T cell immunity

研究衰老与 T 细胞免疫之间的相互作用

• 批准号: 10643160
• 负责人: Riccardo Mezzadra
• 金额: $ 14.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643160
• 关键词: Advisory Committees; Affect; Antitumor Response; Area; Behavior; Bystander Effect; CSF3 gene; Cancer Biology; Cancer Model; Cell Aging; Cell Communication; Cell Cycle Arrest; Cell physiology; Cells; Cellular biology; Data; Development Plans; Engineering; Environment; Exclusion; Faculty; Flow Cytometry; Genetic; Genetic Induction; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune response; Immunity; Immunocompetent; Immunologic Surveillance; Immunology; Immunosuppression; Immunotherapy; Institution; Laboratories; Lead; Macrophage Colony-Stimulating Factor; Malignant neoplasm of gastrointestinal tract; Mediating; Mediator; Memorial Sloan-Kettering Cancer Center; Mentors; Microscopy; Modeling; Mus; Myeloid-derived suppressor cells; Outcome; Pancreatic Ductal Adenocarcinoma; Phenotype; Positioning Attribute; RAS inhibition; Research; Research Personnel; Resources; Role; Scientist; Series; Signal Transduction; Stimulus; Stress; System; T cell infiltration; T cell response; T-Lymphocyte; Testing; Training; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Vocational Guidance; anti-cancer; anti-tumor immune response; cancer cell; cancer genetics; cancer therapy; career development; cell mediated immune response; checkpoint inhibition; collaborative environment; cytokine; design; experimental study; immune checkpoint blockade; in vivo; insight; interest; irradiation; liver cancer model; mouse model; neoantigens; neoplastic cell; novel; novel therapeutics; pancreatic ductal adenocarcinoma model; pharmacologic; programs; rational design; recruit; research and development; senescence; skills; support network; synergism; tool; tumor; tumor microenvironment; tumor progression; Advisory Committees; Affect; Antitumor Response; Area; Behavior; Bystander Effect; CSF3 gene; Cancer Biology; Cancer Model; Cell Aging; Cell Communication; Cell Cycle Arrest; Cell physiology; Cells; Cellular biology; Data; Development Plans; Engineering; Environment; Exclusion; Faculty; Flow Cytometry; Genetic; Genetic Induction; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune response; Immunity; Immunocompetent; Immunologic Surveillance; Immunology; Immunosuppression; Immunotherapy; Institution; Laboratories; Lead; Macrophage Colony-Stimulating Factor; Malignant neoplasm of gastrointestinal tract; Mediating; Mediator; Memorial Sloan-Kettering Cancer Center; Mentors; Microscopy; Modeling; Mus; Myeloid-derived suppressor cells; Outcome; Pancreatic Ductal Adenocarcinoma; Phenotype; Positioning Attribute; RAS inhibition; Research; Research Personnel; Resources; Role; Scientist; Series; Signal Transduction; Stimulus; Stress; System; T cell infiltration; T cell response; T-Lymphocyte; Testing; Training; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Vocational Guidance; anti-cancer; anti-tumor immune response; cancer cell; cancer genetics; cancer therapy; career development; cell mediated immune response; checkpoint inhibition; collaborative environment; cytokine; design; experimental study; immune checkpoint blockade; in vivo; insight; interest; irradiation; liver cancer model; mouse model; neoantigens; neoplastic cell; novel; novel therapeutics; pancreatic ductal adenocarcinoma model; pharmacologic; programs; rational design; recruit; research and development; senescence; skills; support network; synergism; tool; tumor; tumor microenvironment; tumor progression

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.

项目摘要/摘要 候选人：我长期以来的兴趣之一是了解成功的抗肿瘤的调解人 细胞反应。在此应用程序中，我提出了一系列研究，我将研究生研究结合在一起 T细胞生物学的背景，具有我的心理Scott Lowe实验室的专业知识 建模和肿瘤抑制。我在纪念斯隆·肯特林癌症中心的Lowe实验室的研究 （MSKCC）专注于感应是传统抗癌疗法的常见后果， 影响T细胞的功能。在这里，我正在描述过渡到独立的计划，这将使我 至：（i）完成一组导致发现的实验，我将能够继续探索 独立调查员； （ii）获取一套专业知识，并进一步开发了将我分开的研究线 从我现在和过去的导师以及（iii）发展领导实验室所需的一系列专业技能。 研究：癌细胞中的细胞感应是一种应力诱导的程序，可导致稳定的细胞周期 逮捕和分泌多种细胞因子，可能影响其他细胞的行为，包括免疫 细胞。已显示衰老在不同的不同 上下文。细胞感应是抗肿瘤疗法的共同结果，但是通过 哪种感应会改变适应性抗肿瘤免疫反应，这在很大程度上仍然是出乎意料的。这个项目的目的是 使用我开发的新型癌症模型，研究了T细胞的感应后果。 在AIM 1中，我将探讨不同的感应驱动因素如何导致T细胞渗透或T细胞隔离 肿瘤微环境。在AIM 2中，我将探讨一种免疫刺激形式如何影响 T细胞的功能特定于感官和非溶性癌细胞。这些研究将告知 关于感应如何影响抗肿瘤T细胞反应以及如何合理设计更好的反智商 引起衰老的方法。 环境：MSKCC为我提供了实现培训和研究目标的理想环境， 并成功地过渡到学术机构的独立教师职位。我的心理洛博士是 癌症生物学的世界领导者，在肿瘤抑制剂计划，老鼠模型和 功能遗传学。此外，我还与三名成熟科学家组成了一个咨询委员会 相关和互补的专业知识以及对心理的坚定承诺（Pe’er，Rudensky和Rosen博士）， 谁将通过提供宝贵的研究和职业指导来支持我向独立的过渡。一起 在MSKCC的协作环境和广泛的资源中，此支持网络创建 成功完成拟议的研究和职业发展计划的最佳条件。