Defining the barriers to immune surveillance in solid tumors

项目摘要 胰腺癌的预后非常差，它肯定可以从更好的临床中受益。 干预措施。免疫疗法对胰管疾病的临床疗效不佳。 腺癌(PDAC)，尽管它成功地作为各种其他癌症的治疗模块。这一失败 免疫治疗可能是由于在临床和临床前研究中观察到的抗肿瘤T细胞反应迟缓所致。 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 进步。F99阶段项目的长期目标是解决该领域的一些主要问题， 也就是说，新的抗原性是否甚至会触发宿主免疫并影响胰腺癌的肿瘤预后， 在PDAC周围和局部微环境中，T细胞活性的关键障碍是什么？ 提出的研究将利用一种新的PDAC小鼠模型(KPC-OG)来进行时空控制 基因工程新抗原在自发性胰腺癌中的表达 多西环素对照。使用这一强大的临床相关模型，该提案将解决重要问题 关于PDAC中的免疫监测；这些具体包括：(A)处理拟议的“免疫 通过研究抗原性对PDAC进程和宿主免疫反应的影响， (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 抗原启动缺陷，以及(C)研究OVA特异性T细胞与肿瘤的动态相互作用 树突状细胞识别PDAC间质中的运输和抗原提呈功能障碍。结果是 由于其对PDAC免疫逃逸的剖析，这一提议将在该领域产生极大的影响。事实上，这一点 这项工作将在临床上为PDAC和类似的实体肿瘤开发更好的干预措施提供高度的信息。 这一建议引导了PI对可视化宿主之间的交互的长期科学兴趣 免疫和肿瘤发展，以更好地了解实体肿瘤的免疫逃逸机制。 作为这项提议的一部分，计划中的实验将在肿瘤免疫学的几项技术和技能之间架起桥梁。 在这一阶段取得的成果将有利于PI在肿瘤免疫学方面的预期职业生涯。计划中的K00 博士后阶段将包括研究肿瘤引流淋巴结影响的机制。 针对实体肿瘤的系统免疫，特别是确定这些淋巴管如何参与免疫 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，但涉及更多关于肿瘤淋巴中免疫细胞相互作用的尖端定量成像方面的培训 结节和淋巴管。事实上，拟议的跨F99和K00阶段的培训与PI的长期培训相结合 目的研究淋巴管生成功能障碍调节肿瘤进展的更广泛的机制。 他的研究目标是开发针对这种淋巴网络的新型免疫疗法。

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.