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.

项目摘要/摘要 该提案涵盖了一项为期5年的研究和培训计划，以支持瓦滕伯格博士的过渡 独立的研究职业。瓦滕伯格博士的长期目标是领导独立的R01资助 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。为此，瓦滕伯格博士的短期目标是在鼠标领域获得专业知识 建模，转录组学和临床试验。这些努力将得到K08奖的支持，并通过 由Gregory Beatty博士和一个由成功的高级资深组成 科学家。将通过教学课程（包括研讨会和）提供其他正式培训 课程。研究将在宾夕法尼亚大学进行，该大学提供全面 机构资源和强大的研究环境，以培训身体科学家。提案 重点是定义如何开始和破坏癌症中的免疫记忆。研究将使用 临床相关的癌症和患者样品的小鼠模型。免疫记忆对于耐用肿瘤至关重要 免疫疗法诱导的控制。但是，耐用的肿瘤反应在患者中很少见。更好的理解 关于如何开发免疫记忆来为新颖的免疫疗法策略提供信息。初步数据显示 传统的树突状细胞（CDCS）亚型的激活触发小鼠模型中的免疫记忆 胰腺癌。此外，该模型中的免疫记忆取决于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 升高的炎性蛋白与临床结果不良与CDC靶向免疫疗法相关（CD40 胰腺癌患者的激动剂）。此外，在鼠标模型中的完整研究表明 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，限制生产性免疫监视。这是这一点的中心假设 建议不同的CDC亚型坐标CD4+ T细胞存储器，这是耐用肿瘤所必需的 免疫监测，以及与癌症相关的炎性蛋白驱动T细胞免疫进化 CDC亚型失调。瓦滕伯格博士将在以下3个目标中调查这一假设。目标1。 确定CDC亚型对肿瘤特异性CD4+ T细胞记忆的影响。目标2。确定CD4+的作用 T细胞在配位抗肿瘤免疫记忆中。目标3。定义癌症的机制 相关的炎症蛋白驱动CDC命运。该提案的成功完成将提供基本 对癌症免疫生物学的见解并确定新的免疫疗法策略，以改善结果 癌症患者。此外，该提案提供的精通训练和培训将支持瓦滕伯格博士 过渡到独立领导转化研究小组。