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Defining the barriers to immune surveillance in solid tumors

定义实体瘤免疫监视的障碍

基本信息

批准号：
10573195
负责人：
Samarth Hegde
金额：
$ 9.99万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10573195
关键词：
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 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 Lymphatic Lymphatic System Malignant Neoplasms Malignant neoplasm of pancreas Mentors Modality Modeling Mus Outcome Ovalbumin Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Phase Postdoctoral Fellow Pre-Clinical Model Primary Neoplasm Prognosis Proliferating 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 Visualization 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 pancreas imaging 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

项目摘要

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.

项目摘要胰腺癌的预后极差，更好的临床治疗肯定会受益。干预措施。免疫治疗在胰腺导管癌中无法获得显著的临床反应，腺癌（PDAC），尽管其作为各种其他癌症的治疗模块是成功的。的失败免疫疗法的失败可能是由于在临床和临床前研究中观察到的抗肿瘤T细胞应答受阻。关于抗原导向的抗肿瘤免疫监视如何在PDAC上被破坏，我们知之甚少。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-新抗原性是否甚至触发宿主免疫并影响胰腺癌的肿瘤结果， PDAC外周和局部微环境中T细胞活性的关键障碍是什么？本研究将利用一种新的PDAC小鼠模型（KPC-OG），使用免疫组织化学技术在自发性胰腺癌中表达工程化新抗原（OVA）强力霉素对照。使用这个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;这些将具体包括（a）解决拟议的“免疫通过研究抗原性对PDAC进展和宿主免疫应答的影响， (b)分析PDAC相关淋巴系统中OVA特异性T细胞的活化和扩增，以评估抗原引发缺陷，和（c）研究OVA特异性T细胞和肿瘤之间的动态相互作用树突状细胞来鉴定PDAC基质中的运输和抗原呈递功能障碍。成果由于其对PDAC免疫逃逸的剖析，来自该提议的方法将在该领域具有高度影响力。这确这项工作将在临床上为PDAC和类似实体瘤开发更好的干预措施提供大量信息。这一提议引导了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，计划进行的实验将连接肿瘤免疫学中的几种技术，在此阶段获得的经验将有利于PI在肿瘤免疫学方面的预期职业生涯。K 00计划博士后阶段将涉及研究肿瘤引流淋巴结影响针对实体瘤的全身免疫，特别是确定这些肿瘤如何在免疫系统中被吸收，逃生机制博士后培训的设想是建立在PI现有的肿瘤免疫学基础上技能，但涉及肿瘤淋巴中免疫细胞相互作用的尖端定量成像的更多培训淋巴结和淋巴管。事实上，F99和K 00阶段的拟议培训与PI的长期目的是研究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这种淋巴网络的新型免疫疗法。