Immune Evasion in Pancreatic Cancer

胰腺癌的免疫逃避

• 批准号: 9805485
• 负责人: Mark Stephen Diamond
• 金额: $ 20.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805485
• 关键词: Address; Advisory Committees; Agonist; Antigen Presentation Pathway; Antigens; Area; Basic Science; CD8-Positive T-Lymphocytes; Cancer Burden; Cancer Etiology; Cancer Immunology Science; Cell Line; Clinical; Colorectal; Combination immunotherapy; Combined Modality Therapy; Communities; Cross-Priming; Data; Dendritic Cells; Development Plans; Diamond; Disease; Engineering; Environment; Epithelial; Exhibits; Fibrinogen; Five-Year Plans; Functional disorder; Genes; Heterogeneity; Human; Immune; Immune Evasion; Immune response; Immunity; Immunologics; Immunosuppression; Immunotherapy; In complete remission; Individual; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentors; Mentorship; Mesenchymal; Minority; Modeling; Mus; Mutation; Ovalbumin; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pennsylvania; Peritoneal; Peritoneum; Phenotype; Physicians; Process; Recurrence; Refractory; Regimen; Reporting; Research; Research Training; Resistance; Resources; SLEB2 gene; Scientist; Snails; System; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Training; Treatment Efficacy; Tumor Escape; Tumor Immunity; Tumor-Derived; Tumor-infiltrating immune cells; Universities; Up-Regulation; Work; base; cancer type; career; career development; cellular engineering; chemokine; defined contribution; genetic signature; immune checkpoint; immunogenic; improved; in vivo; innovation; insight; interest; knock-down; mortality; mouse model; neoantigens; neoplastic cell; novel strategies; oncology; outcome forecast; overexpression; programs; research and development; response; subcutaneous; tool; trafficking; transcription factor; transcriptomics; tumor; tumor microenvironment

PROJECT SUMMARY This proposal describes a five-year plan involving career development, didactic training, and basic research focused on mechanisms of immune evasion in pancreatic cancer, which will facilitate the independent physician scientist career of Dr. Mark Diamond in the area of cancer immunology. The candidate is interested in understanding barriers to effective antitumor immunity against pancreatic ductal adenocarcinoma (PDAC), a deadly cancer that is poorly T cell-infiltrated and refractory to current immunotherapy. Using tumors derived from the ‘KPC’ murine model, Dr. Diamond has shown that PDAC cells engineered to be highly antigenic exhibit selective immune escape in the pancreatic and peritoneal microenvironments; and that outgrowth resulted from poor tumor-specific T cell priming by classical dendritic cells (cDCs) rather than antigen loss or tumor immunoediting. He has additionally modeled acquired resistance following combination immunotherapy of subcutaneous tumors, as prior studies have demonstrated the efficacy of CD40 agonist-based regimens that promote T cell priming and can induce durable regressions. Studying late tumor recurrences following complete responses to therapy, the candidate has shown that such tumors exhibit acquired immunotherapy resistance and upregulation of genes in the epithelial-mesenchymal transition (EMT) pathway. Based on these data, Dr. Diamond hypothesizes that antitumor immunity to PDAC is limited by both tumor-cell intrinsic processes including EMT, and microenvironmental barriers within the pancreas limiting CD8+ T cell priming by cDC1s. The candidate will address this hypothesis in the following two specific aims: (Aim 1) Define the contribution of tumor cell plasticity mediated by EMT-inducing transcription factors on acquired resistance to immunotherapy, and (Aim 2) Determine whether cDC1 dysfunction within the pancreatic microenvironment limits CD8+ T cell priming against highly antigenic tumors. Dr. Diamond has assembled a team of successful physician scientists at the University of Pennsylvania, including his primary mentor Dr. Robert Vonderheide, to serve as his advisory committee and oversee his research and career development. Dr. Diamond will also benefit from an excellent institutional environment that includes unique resources, mentorship, and a strong scientific community. The comprehensive career development plan and intensive research training outlined in this proposal will allow Dr. Diamond to acquire the necessary tools for an independent career as a physician scientist in oncology.

项目摘要 该建议描述了一个五年计划，涉及职业发展，教学培训和基础研究 专注于胰腺癌免疫进化的机制，这将促进独立医生 马克·戴蒙德博士在癌症免疫学领域的科学家职业。候选人对 了解有效抗肿瘤免疫的障碍抗胰腺导管腺癌（PDAC），A 致命的癌症，T细胞浸润且对当前免疫疗法难治性。使用从 Diamond博士是“ KPC”鼠模型，表明PDAC细胞设计为高度抗原的展览 胰腺和腹膜微环境中的选择性免疫逃逸；这种产物由 经典树突状细胞（CDC）而不是抗原丧失或肿瘤的肿瘤特异性T细胞启动不良 免疫程序。在组合免疫疗法之后，他还建模了获得的抗药性 皮下肿瘤，因为先前的研究表明，基于CD40激动剂的方案的效率是 促进T细胞启动并诱导持久的回归。在完成后研究晚期肿瘤复发 对治疗的反应，候选人表明，这种肿瘤暴露于获得的免疫疗法耐药性 和上皮 - 间质转变（EMT）途径中基因的上调。基于这些数据，博士 钻石假设对PDAC的抗肿瘤免疫受到两个肿瘤固有过程的限制 包括EMT和胰腺中的微环境屏障，限制了CDC1的CD8+ T细胞启动。这 候选人将在以下两个具体目的中解决这一假设：（目标1）定义肿瘤的贡献 通过EMT诱导转录因子对免疫疗法的抗性介导的细胞可塑性，以及 （AIM 2）确定胰腺微环境内的CDC1功能障碍是否限制了CD8+ T细胞启动 针对高度抗原性肿瘤。 Diamond博士在 宾夕法尼亚大学，包括他的主要导师罗伯特·沃德海德博士，担任他的咨询 委员会并监督他的研究和职业发展。 Diamond博士还将受益于优秀 机构环境，包括独特的资源，指导和强大的科学界。 该提案中概述的全面职业发展计划和强化研究培训将允许博士 钻石以作为肿瘤学物理科学家的独立职业获得必要的工具。