Cellular and microenvironmental mechanisms linking aging to tumor control

项目摘要。 research.癌症发病率随着年龄的增长而急剧增加。虽然平均预期寿命继续增长， 上升，一个后果是癌症病例预计将在2010年至2030年间增长45%，突出显示 迫切需要研究衰老生理学和肿瘤发生之间的交叉。但大多数 癌症研究是使用年轻的成年小鼠作为临床前癌症模型进行的， 环境风险因素，如衰老，对肿瘤发生的关键特征无法衡量。免疫 系统特别容易随着老化而功能衰退。许多不同种类的免疫细胞可以 发现浸润性肿瘤，其中CD8 + T细胞特别可以识别并选择性地杀死癌细胞， 识别肿瘤与正常组织不同的特征。尽管研究表明衰老会减少 细菌和病毒感染后CD8 + T细胞增殖和效应子应答，衰老对抗CD8 + T细胞增殖的作用， 肿瘤免疫仍然是一个主要的黑匣子。根据我们对年轻和老年小鼠肿瘤的初步数据， 我们假设CD8 + T细胞的抗肿瘤免疫受损有助于衰老过程中的肿瘤发生。到 为了验证这一假设，Aim 1将首先开发小鼠模型来研究衰老、癌症和抗肿瘤免疫， 然后使用流式细胞术和单细胞免疫分析技术， RNA测序。在目标2中，我们将定义老年肿瘤微环境中的代谢变化，然后测试 这些是否是导致CD8 + T细胞功能障碍的原因。最后，目标3将确定是否增强代谢 通过转录组学和代谢组学分析鉴定的免疫细胞中的途径可以改善肿瘤控制 在老化过程中。通过揭示肿瘤微环境如何随年龄变化以及对抗肿瘤的影响 免疫，这些研究将确定机制，驱动T细胞功能障碍的肿瘤，可能是针对 改善癌症预防和治疗。 候选人Alison Ringel博士是本研究提案的PI。她曾担任博士后研究员 在过去的五年里，她在哈佛医学院，在那里她试图了解分子 这些机制驱动肿瘤发生，以应对环境癌症风险因素，如肥胖。她是 在面试终身教职职位的过程中， 发展计划，这将使她过渡到一个独立的研究生涯，她将发展她的 衰老和肿瘤发生的研究项目。她的目标是成为癌症免疫学的领导者， 一种创新的系统生物学方法来解剖肿瘤生态位，这将使她的独立工作与众不同。 与她的博士后导师们不同她的长期目标是领导一个独立的癌症研究项目 致力于发现肿瘤内调节局部免疫反应的分子机制， 肿瘤进展。

Project Summary. Research. Cancer incidence increases dramatically with age. While the average life expectancy continues to rise, one consequence is that cancer cases are predicted to grow by 45% between 2010 and 2030, highlighting the critical need to study the intersection between aging physiology and tumorigenesis. However, the majority of cancer research is performed using young adult mice as pre-clinical cancer models, where impact of environmental risk factors, like aging, on key features of tumorigenesis cannot be measured. The immune system is especially vulnerable to functional decline with aging. Many different kinds of immune cells can be found infiltrating tumors, where CD8+ T cells in particular can identify and selectively kill cancer cells by recognizing tumor features that differ from normal tissue. Although studies have shown that aging diminishes CD8+ T cell proliferation and effector responses following bacterial and viral infections, the role of aging on anti- tumor immunity is still a major black box. Based on our preliminary data in tumors from young and aged mice, we hypothesize that impaired anti-tumor immunity by CD8+ T cells contributes to tumorigenesis during aging. To test this hypothesis, Aim 1 will first develop mouse models to study aging, cancer, and anti-tumor immunity, and then identify mechanisms that alter immune cell function in the tumor niche using flow cytometry and single cell RNA-sequencing. In Aim 2, we will define metabolic changes in the aged tumor microenvironment and then test whether these are causal for CD8+ T cell dysfunction. Finally, Aim 3 will determine whether enhancing metabolic pathways in immune cells identified by transcriptomic and metabolomic analysis can improve tumor control during aging. By revealing how the tumor microenvironment changes with age and the impact on anti-tumor immunity, these studies will identify mechanisms that drive T cell dysfunction in tumors that may be targeted to improve cancer prevention and therapy. Candidate. Dr. Alison Ringel, PhD, is the PI for this research proposal. She has worked as a postdoctoral fellow for the past five years at Harvard Medical School, where she has sought to understand the molecular mechanisms that drive tumorigenesis in response to environmental cancer risk factors such as obesity. She is in the process of interviewing for tenure-track faculty positions and has mapped out a detailed professional development plan that will enable her to transition to an independent research career where she will develop her research program on aging and tumorigenesis. She aims to become a leader in cancer immunology by applying an innovative systems biology approach to dissect the tumor niche, which will distinguish her independent work from that of her postdoctoral mentors. Her long-term goal is to lead an independent cancer research program dedicated to the discovery of molecular mechanisms within tumors that regulate local immune responses and tumor progression.