Investigating CD4+ T cell memory in cancer immunotherapy

项目摘要/摘要 这项提议包括一项为期5年的研究和培训计划，以支持Wtenberg博士过渡到 独立的研究生涯。瓦滕伯格博士的长期目标是领导一个由R01资助的独立项目 学术机构的研究计划，进行以定义相关癌症为重点的研究 免疫生物学。为了实现这一目标，瓦滕伯格博士的短期目标是获得MICE领域的专业知识 建模、转录学和临床试验。这些努力将得到K08奖的支持，并通过 由Gregory Beatty博士和由成功的高年级学生组成的导师委员会提供 科学家。将通过教学课程提供额外的正式培训，包括讲习班和 课程。研究将在宾夕法尼亚大学进行，该大学提供了全面的 培训内科科学家的机构资源和健全的研究环境。这项建议 重点是定义癌症中的免疫记忆是如何启动和破坏的。研究将使用以下方法进行 临床上相关的癌症小鼠模型和患者样本。免疫记忆是持久肿瘤的关键 免疫治疗诱导的对照。然而，持久的肿瘤反应在患者中很少见。更好地理解 需要了解免疫记忆是如何发展的，以便为新的免疫治疗策略提供信息。初步数据显示 常规树突状细胞(CDCs)亚型的激活触发小鼠模型的免疫记忆 胰腺癌。此外，该模型中的免疫记忆依赖于CD4+T细胞，而不是CD8+ T细胞--免疫系统的典型效应细胞。其他先前的工作表明，从系统的角度来看 CDC靶向免疫治疗(CD40)与炎性蛋白升高相关的不良临床结果 激动剂)治疗胰腺癌。此外，对小鼠模型的补充性研究表明 炎性细胞因子IL-6与CDC失调相关。这些发现表明炎症性疾病 蛋白质导致CDC功能障碍，限制了生产性免疫监控。这是这一观点的核心假设。 建议不同的CDC亚型协调CD4+T细胞记忆，这是持久肿瘤所必需的 免疫监控，癌症相关炎症蛋白通过 CDC亚型失调。瓦滕伯格博士将从以下三个方面研究这一假说。目标1。 确定CDC亚型对肿瘤特异性CD4+T细胞记忆的影响。目的2.确定CD4+的作用 T细胞在协同抗肿瘤免疫记忆中的作用目标3.定义癌症的机制-- 相关的炎性蛋白决定CDC的命运。成功完成这项提案将提供基本的 深入了解癌症免疫生物学并确定新的免疫治疗策略，以改善患者的预后 癌症患者。此外，这项提案提供的指导和培训将支持瓦滕伯格博士的 过渡到独立，领导一个翻译研究小组。

Project Summary/Abstract This proposal encompasses a 5-year research and training plan to support the transition of Dr. Wattenberg to an independent research career. Dr. Wattenberg’s long-term goals are to lead an independent R01-funded research program at an academic institution, conducting research focused on defining relevant cancer immunobiology. To achieve this, Dr. Wattenberg’s short-term goals are to gain expertise in the areas of mouse modeling, transcriptomics and clinical trials. These efforts will be supported by the K08 award and through mentorship provided by Dr. Gregory Beatty and a mentorship committee consisting of successful senior scientists. Additional formal training will be provided through a didactic curriculum, including workshops and courses. Research will be conducted at the University of Pennsylvania, which provides comprehensive institutional resources and a robust research environment for the training of physician-scientists. The proposal focuses on defining how immune memory in cancer is initiated and disrupted. Studies will be performed using clinically relevant mouse models of cancer and patient samples. Immune memory is crucial for durable tumor control induced by immunotherapy. However, durable tumor responses are rare in patients. Better understanding of how immune memory develops is needed to inform novel immunotherapy strategies. Preliminary data show that activation of conventional dendritic cell (cDCs) subtypes triggers immunological memory in mouse models of pancreatic cancer. Further, immunological memory in this model is dependent on CD4+ T cells and not CD8+ T cells - the prototypical effector cells of the immune system. Additional prior work shows that systemically elevated inflammatory proteins associate with poor clinical outcomes to cDC targeted immunotherapy (CD40 agonist) in patients with pancreatic cancer. Moreover, complementary studies in mouse models show the inflammatory cytokine IL-6 to associate with cDC dysregulation. These findings suggest that inflammatory proteins drive cDC dysfunction, limiting productive immunosurveillance. It is the central hypothesis of this proposal that distinct cDC subtypes coordinate CD4+ T cell memory, which is necessary for durable tumor immunosurveillance, and that cancer-associated inflammatory proteins drive T cell immune evasion by dysregulating cDC subtypes. Dr. Wattenberg will investigate this hypothesis in the following 3 aims. Aim 1. Determine the impact of cDC subtypes on tumor specific CD4+ T cell memory. Aim 2. Determine the role of CD4+ T cells in coordinating anti-tumor immunological memory. Aim 3. Define the mechanisms by which cancer- associated inflammatory proteins drive cDC fate. Successful completion of this proposal will provide fundamental insights into cancer immunobiology and identify novel immunotherapy strategies to improve outcomes for patients with cancer. Further, the mentorship and training provided by this proposal will support Dr. Wattenberg’s transition to independence leading a translational research group.