Defining the barriers to immune surveillance in solid tumors

定义实体瘤免疫监视的障碍

• 批准号: 10355526
• 负责人: Samarth Hegde
• 金额: $ 9.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355526
• 关键词: Activation Analysis; Adaptive Immune System; Address; Adoptive Cell Transfers; Antigen Presentation; Antigens; Antitumor Response; CD8-Positive T-Lymphocytes; Carcinoma; Cell Communication; Chronic; Clinic; Clinical; Clinical Research; Collaborations; Defect; Dendritic Cells; Dendritic cell tumor; Disease Outcome; Disease Progression; Dissection; Doxycycline; Education; Engineering; Failure; Functional disorder; Future; Genetic Models; Goals; Image; Imaging Techniques; Immune; Immune response; Immunity; Immunologic Surveillance; Immunologics; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Infiltration; Intervention; Label; Learning; Lesion; Letters; Lymphangiogenesis; Lymphatic; Lymphatic System; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Modality; Modeling; Mus; Outcome; Ovalbumin; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phase; Pre-Clinical Model; Primary Neoplasm; Prognosis; Reporter; Research; Research Project Grants; Sampling; Signal Transduction; Solid Neoplasm; Survival Rate; System; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Training; Transcriptional Activation; Transplantation; Tumor Escape; Work; adaptive immune response; anergy; antigen-specific T cells; cancer imaging; career; clinically relevant; cytotoxicity; draining lymph node; experimental study; human model; immune imaging; immunogenic; improved; innovation; interest; intravital imaging; lymph nodes; lymphatic vessel; mouse model; neoantigens; next generation; novel; pancreatic cancer cells; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; post-doctoral training; pre-doctoral; preclinical study; quantitative imaging; recruit; response; skills; spatiotemporal; success; trafficking; tumor; tumor immunology; tumor microenvironment; tumor progression

Project Summary The prognosis for pancreatic cancer is extremely poor, and it can surely benefit from better clinical interventions. Immunotherapy has been ineffective in achieving significant clinical responses in pancreatic ductal adenocarcinomas (PDAC), despite its success as a treatment module for various other cancers. This failure of immunotherapy is likely due to the stunted anti-tumor T cell response observed in clinical and pre-clinical studies. Very little is known about how antigen-directed anti-tumor immune surveillance becomes undermined over PDAC progression. The long term aim of the F99 phase project is to address some major questions in the field, namely—Does neoantigenicity even trigger host immunity and influence tumor outcome in pancreatic cancer, and what are the key barriers to T cell activity in the periphery and local microenvironment of PDAC? The proposed studies will exploit a novel mouse model of PDAC (KPC-OG) to spatiotemporally control expression of an engineered neoantigen (OVA) in spontaneously developing pancreatic cancer using doxycycline control. Using this robust clinically-relevant model, the proposal will address important questions regarding immune surveillance in PDAC; these would specifically include (a) addressing the proposed ‘immune privilege’ of pancreata by studying the effect of antigenicity on PDAC progression and host immune response, (b) analyzing activation and expansion of OVA-specific T cells in PDAC-associated lymphatic system to assess antigen-priming defects, and (c) studying the dynamic interaction between OVA-specific T cells and tumor dendritic cells to identify trafficking and antigen-presentation dysfunctions in the PDAC stroma. The outcomes from this proposal will be highly impactful in the field due to its dissection of PDAC immune escape. Indeed, this work will be highly informative in the clinic for developing better interventions for PDAC and similar solid tumors. This proposal channels the PI’s long-term scientific interest of visualizing interactions between host immunity and developing tumors to better understand mechanisms of immune escape in solid tumors. Experiments planned as part of this proposal will bridge several techniques in tumor immunology, and skills gained in this phase will be advantageous for the PI’s intended career in oncoimmunology. The planned K00 postdoctoral phase will involve studying the mechanisms by which tumor-draining lymph nodes influence systemic immunity against solid tumors, specifically determining how these lymphatics get co-opted in immune escape mechanisms. The postdoctoral training is envisioned to build upon the PI’s existing tumor-immunology skillset, but involve more training in cutting-edge quantitative imaging of immune cell interactions in tumor lymph nodes and lymphatic vessels. Indeed, proposed training across the F99 & K00 phases tie into the PI’s long-term goal to examine the broader mechanisms by which lymphangiogenic dysfunctions regulate tumor progression, and his research objective to develop novel immunotherapy targeting this lymphatic network.

项目概要 胰腺癌的预后极差，它肯定可以受益于更好的临床 干预措施。免疫疗法无法有效地在胰腺导管中获得显着的临床反应 腺癌（PDAC），尽管它作为各种其他癌症的治疗模块取得了成功。这次失败的 免疫疗法可能是由于临床和临床前研究中观察到的抗肿瘤 T 细胞反应迟缓所致。 关于抗原导向的抗肿瘤免疫监视如何因 PDAC 而受到破坏，人们知之甚少 进展。 F99阶段项目的长期目标是解决该领域的一些主要问题， 即——新抗原性是否会触发宿主免疫并影响胰腺癌的肿瘤结果， PDAC外围和局部微环境中T细胞活性的关键障碍是什么？ 拟议的研究将利用一种新型 PDAC 小鼠模型（KPC-OG）来进行时空控制 工程化新抗原（OVA）在自发发展的胰腺癌中的表达 多西环素控制。使用这种强大的临床相关模型，该提案将解决重要问题 关于 PDAC 中的免疫监视；这些具体包括 (a) 解决拟议的“免疫 通过研究抗原性对 PDAC 进展和宿主免疫反应的影响来确定胰腺的特权， (b) 分析 PDAC 相关淋巴系统中 OVA 特异性 T 细胞的激活和扩增，以评估 抗原引发缺陷，以及 (c) 研究 OVA 特异性 T 细胞与肿瘤之间的动态相互作用 树突状细胞识别 PDAC 基质中的运输和抗原呈递功能障碍。结果 由于对 PDAC 免疫逃逸的剖析，该提案将在该领域产生巨大影响。确实，这 这项工作将为临床开发更好的 PDAC 和类似实体瘤干预措施提供大量信息。 该提案传达了 PI 对可视化宿主之间相互作用的长期科学兴趣 免疫和发展中的肿瘤，以更好地了解实体瘤中的免疫逃逸机制。 作为该提案的一部分计划的实验将连接肿瘤免疫学和技能中的多种技术 在此阶段获得的成果将有利于 PI 在肿瘤免疫学领域的预期职业生涯。计划中的K00 博士后阶段将涉及研究肿瘤引流淋巴结影响的机制 针对实体瘤的全身免疫，特别是确定这些淋巴管如何参与免疫 逃逸机制。博士后培训预计以 PI 现有的肿瘤免疫学为基础 技能，但涉及更多肿瘤淋巴中免疫细胞相互作用的尖端定量成像培训 淋巴结和淋巴管。事实上，拟议的跨 F99 和 K00 阶段的培训与 PI 的长期目标相关 目标是检查淋巴管生成功能障碍调节肿瘤进展的更广泛机制， 他的研究目标是开发针对该淋巴网络的新型免疫疗法。