Investigating CD4+ T cell memory in cancer immunotherapy

研究癌症免疫治疗中的 CD4 T 细胞记忆

• 批准号: 10739583
• 负责人: Max Wattenberg
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739583
• 关键词: Agonist; Apoptosis; Area; Automobile Driving; Award; CAR T cell therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cancer Model; Cell Communication; Cell Survival; Cells; Clinical; Clinical Trials; Cues; Cytokine Receptors; Data; Dendritic Cells; Development; Educational workshop; Effector Cell; Engineering; Environment; Functional disorder; Funding; Generations; Genetic Transcription; Goals; Human; Immune; Immune Evasion; Immune response; Immune system; Immunologic Memory; Immunologic Surveillance; Immunotherapy; Infiltration; Inflammation; Inflammatory; Institution; Interleukin-6; Knockout Mice; Lead; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Memory; Mentors; Mentorship; Modeling; Mus; Myelogenous; Natural Immunity; Neoplasm Metastasis; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Pennsylvania; Phenotype; Physicians; Play; Population; Process; Productivity; Proteins; Research; Resistance; Resources; Role; STAT3 gene; Sampling; Scientist; Senior Scientist; Signal Transduction; Survival Rate; T-Lymphocyte; TNF gene; TNFRSF5 gene; Testing; Training; Transgenic Mice; Translational Research; Tumor Immunity; Universities; Work; advanced pancreatic cancer; cancer immunobiology; cancer immunotherapy; career; cell type; clinically relevant; conditional knockout; cytokine; cytotoxic CD8 T cells; didactic education; immune checkpoint blockade; immunogenic; improved; improved outcome; insight; melanoma; memory CD4 T lymphocyte; memory recall; mouse model; neoplastic cell; novel; pancreatic cancer model; pancreatic cancer patients; pharmacologic; pre-clinical; programs; response; transcriptomics; tumor; tumor eradication; tumor microenvironment

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.

项目总结/摘要 该提案包括一项为期5年的研究和培训计划，以支持Wattenberg博士过渡到 独立的研究生涯。Wattenberg博士的长期目标是领导一个独立的R 01资助的 学术机构的研究计划，进行研究，重点是定义相关癌症 免疫生物学为了实现这一目标，Wattenberg博士的短期目标是获得小鼠领域的专业知识， 建模、转录组学和临床试验。这些努力将得到K 08奖的支持，并通过 由格雷戈里·比蒂博士提供的导师和一个由成功的高级 科学家将通过教学课程，包括讲习班， 课程研究将在宾夕法尼亚大学进行，该大学提供全面的 机构资源和一个强有力的研究环境，以培养医生和科学家。该提案 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 临床相关的癌症小鼠模型和患者样品。免疫记忆对于持久的肿瘤至关重要 免疫治疗诱导的控制。然而，持久的肿瘤反应在患者中是罕见的。更好地理解 免疫记忆是如何发展的，这是为新的免疫治疗策略提供信息所必需的。初步数据显示 在小鼠模型中，常规树突状细胞（cDCs）亚型的激活触发了免疫记忆， 胰腺癌此外，该模型中的免疫记忆依赖于CD 4 + T细胞，而不是CD 8 + T细胞。 T细胞-免疫系统的原型效应细胞。额外的先前工作表明，系统地 升高的炎症蛋白与cDC靶向免疫治疗（CD 40）的不良临床结局相关 在胰腺癌患者中，此外，在小鼠模型中的补充研究表明， 炎性细胞因子IL-6与cDC失调相关。这些发现表明，炎症 蛋白质驱动cDC功能障碍，限制了有效的免疫监视。这是其中的核心假设 不同的cDC亚型协调CD 4 + T细胞记忆，这是持久肿瘤所必需的 免疫监视和癌症相关炎性蛋白驱动T细胞免疫逃避， cDC亚型失调。Wattenberg博士将在以下3个目标中研究这一假设。目标1. 确定cDC亚型对肿瘤特异性CD 4 + T细胞记忆的影响。目标2.确定CD 4+的作用 协调抗肿瘤免疫记忆的T细胞。目标3.明确癌症的发病机制- 相关炎症蛋白驱动cDC命运。成功完成此提案将为 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 癌症患者。此外，本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。