Contribution of Innate Immune Sensing on Head and Neck Squamous Cell Carcinoma (HNSCC)

先天免疫感应对头颈鳞状细胞癌 (HNSCC) 的贡献

基本信息

批准号：
10536327
负责人：
Dakota Michael Reinartz
金额：
$ 3.96万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-14 至 2024-09-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536327
关键词：
Address Alcohols Antigens Automobile Driving Binding Biological Assay Biological Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Carcinogens Cardiac Myocytes Cell Survival Cells Chronic Colon Carcinoma Complex Data Dendritic Cells Development Environment Epithelial Equilibrium Excision Experimental Models Exposure to Flow Cytometry Genes Goals Growth Head and Neck Squamous Cell Carcinoma Hematopoietic Human Immune Immune system In Vitro Infiltration Inflammation Inflammatory Interferon Type II Interleukin-1 beta Interleukin-10 Interleukin-18 Lead Link MAP Kinase Gene Malignant Neoplasms Measures Molecular Mucous Membrane Mus Nose Oral Oral cavity Pathway interactions Pattern recognition receptor Peptides Pharyngeal structure Phosphorylation Phosphotransferases Physiologic pulse Physiological Preventive measure Preventive screening Production Proteins Proto-Oncogene Proteins c-akt RNA Research Risk Factors Role STAT1 gene Shapes Survival Rate System T cell differentiation T cell response T-Cell Activation T-Lymphocyte Testing Tissues Tobacco Tongue Neoplasms United States adaptive immunity cancer type carcinogenesis cytokine draining lymph node ds-DNA experimental study fludarabine immunoregulation improved in vivo inhibitor innate immune sensing neutralizing antibody new therapeutic target novel prevent recruit sensor transcription factor transcriptome sequencing tumor

项目摘要

Dakota Reinartz Contribution of an innate immune sensor on Head and Neck Squamous Cell Carcinoma (HNSCC) The role of the intracellular pattern recognition receptor, AIM2, in inflammation associated cancers remains unclear. Preliminary data suggests that Aim2-/- mice treated with the oral carcinogen 4NQO continuously as an experimental model of HNSCC display larger tumors, heightened IFNγ and increased recruitment of draining lymph node IFNγ-positive CD4 and CD8 T cells compared to wild type counterparts. RNA sequencing of whole tissue RNA revealed an enrichment of IFNγ-stimulated genes in 4NQO-treated Aim2-/- mice, further suggesting AIM2 restricts IFNγ. Interestingly, removal of 4NQO lead to enhanced tissue Il10 in Aim2-/- mice, which required with hematopoietic expression of AIM2 in vivo. Consistent with these findings, preliminary data indicates in vitro Th1-differented Aim2-/- CD4 T cells produce more IFNγ and IL-10 than wild type controls. We hypothesize that AIM2 restricts HNSCC growth by preventing the switch from CD4 T cell production of pro-inflammatory IFNγ to immunosuppressive IL-10. To address this hypothesis, first we will determine the molecular mechanism by which AIM2 modulates the IFNγ and IL-10 balance in Th1 CD4 T cells. Second, we will determine the mechanism and cellular contribution by which AIM2 restricts HNSCC development in vivo. Our proposed research will uncover the molecular and cellular mechanisms by which AIM2 and inflammation drive HNSCC, which could identify targets for novel therapeutics or preventative screens, while also defining a novel biological function for AIM2 in shaping adaptive immunity.

达科塔·赖纳茨先天免疫传感器对头颈鳞状细胞癌 (HNSCC) 的贡献细胞内模式识别受体 AIM2 在炎症相关癌症中的作用初步数据表明 Aim2-/- 小鼠接受了口服致癌物 4NQO 治疗。作为 HNSCC 的实验模型，不断显示出更大的肿瘤、增强的 IFNγ 和增加的与野生型供体相比，引流淋巴结 IFNγ 阳性 CD4 和 CD8 T 细胞的募集。全组织 RNA 的 RNA 测序揭示了 4NQO 处理的 IFNγ 刺激基因的富集 Aim2-/- 小鼠，进一步表明 AIM2 隐式限制 IFNγ，去除 4NQO 会导致组织增强。 Il10在Aim2-/-小鼠中的表达与AIM2体内造血表达的要求一致。研究结果，初步数据表明体外 Th1 分化的 Aim2-/- CD4 T 细胞产生更多的 IFNγ 和 IL-10 与野生型对照相比，我们发现 AIM2 通过阻止 CD4 的转换来限制 HNSCC 的生长。 T 细胞产生促炎性 IFNγ 和免疫抑制性 IL-10。将确定 AIM2 调节 Th1 CD4 T 中 IFNγ 和 IL-10 平衡的分子机制其次，我们将确定 AIM2 限制 HNSCC 的机制和细胞贡献。我们提出的研究将揭示其分子和细胞机制。 AIM2 和炎症驱动 HNSCC，这可以确定新治疗或预防的靶标筛选，同时还定义了 AIM2 在塑造适应性免疫方面的新生物学功能。