Enhance Immunoprevention by Blocking Early Expansion of Suppressive Myeloid Cells - Supplement Proposal

通过阻止抑制性骨髓细胞的早期扩增来增强免疫预防 - 补充提案

• 批准号: 10281851
• 负责人: John Chadwick Brenner
• 金额: $ 25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281851
• 关键词: Award; CD4 Positive T Lymphocytes; Cells; Data Set; Disease; Erythroplasia; Excision; Exhibits; Genetically Engineered Mouse; Genomics; Head and Neck Cancer; Histologic; Immune; Immunologic Surveillance; Immunologics; Immunooncology; Immunoprevention; Infiltration; Intraepithelial Neoplasia; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Metabolic; Modeling; Morbidity - disease rate; Mucous Membrane; Myeloid-derived suppressor cells; Operative Surgical Procedures; Oral; Oral Leukoplakia; Parents; Patients; Prevention; Regimen; Time; effective therapy; head and neck cancer patient; high risk; high risk population; human disease; immune checkpoint blockade; loss of function; new technology; novel; oral cavity epithelium; orofacial; parent project; premalignant; programs; public health relevance; single-cell RNA sequencing; tumor-immune system interactions

PROJECT SUMMARY Immune checkpoint blockade has proven an effective treatment for a subset of head and neck cancer (HNC) patients. However, over 85% of the patients cannot benefit from this strategy, largely due to the highly immunosuppressive tumor microenvironment (TME) in established cancers. Oral leukoplakias / Oral Epithelial Dysplasias (OEDs) precede HNC and offer a unique time window for disease eradication. However, surgical resection in the orofacial region results in significant morbidity and function loss, and more importantly, cannot reverse field cancerization. A subset of OEDs transform into malignancy despite vigilant follow-ups. Frequent immune cell infiltration is a common feature of OEDs, however, little is known about when and how OEDs evade from immuno-surveillance and reach a point-of-no-return. Through the support of the parent award, we constructed unique genetically engineered mouse models, which can model a spectrum of OED/HNC lesions with high-fidelity histologic and immunophenotypic resemblance to human diseases. In this supplement, two immunoprevention teams within the Immuno-Oncology Translational Network will integrate a recently developed immune profiling analytical pipeline for single-cell RNA-Seq data sets to assess the prevention effects of a novel combination, which aims to mitigate the early expansion of suppressive myeloid cells and to enrich effector CD4+ T-cells. The new technologies developed through the supplement will strengthen the two parent projects and inform new promising immunoprevention assets for genetically high-risk OEDs.

项目摘要 免疫检查点阻断已被证明是一种有效的治疗头颈部癌症的方法 (HNC)患者然而，超过85%的患者不能从这种策略中受益，主要是由于高度的 免疫抑制肿瘤微环境（TME）在已建立的癌症中的作用。口腔白斑/口腔上皮 发育不良（OED）先于HNC，为疾病根除提供了独特的时间窗。然而，手术 口面区域的切除导致显著的发病率和功能丧失，更重要的是， 反向场癌变。一个子集的OED转化为恶性肿瘤，尽管警惕后续。频繁 免疫细胞浸润是OEDs的一个共同特征，然而，关于OEDs何时以及如何浸润却知之甚少。 逃避免疫监视，走上不归路通过家长奖的支持，我们 构建了独特的基因工程小鼠模型，可以模拟一系列OED/HNC病变 在组织学和免疫表型上与人类疾病高度相似。在这篇文章中，两个 免疫肿瘤转化网络内的免疫预防团队将在最近整合一个 为单细胞RNA-Seq数据集开发免疫分析管道，以评估预防 一种新的组合，其目的是减轻抑制性骨髓细胞的早期扩增， 富集效应CD 4 + T细胞。通过补充开发的新技术将加强这两个 父项目，并为遗传高风险OED提供新的有前途的免疫预防资产。