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

• 批准号: 10704560
• 负责人: Dakota Michael Reinartz
• 金额: $ 4.12万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/10704560
• 关键词: Address; Alcohol consumption; Antigens; Automobile Driving; Binding; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Carcinogens; Cardiac Myocytes; Cell Separation; Cell Survival; Cells; Chronic; Colon Carcinoma; Complex; Data; Dendritic Cells; Development; Environment; Epithelial Cells; Equilibrium; Excision; Experimental Models; Exposure to; Flow Cytometry; Genes; Goals; Growth; HPV-negative head and neck cancer; Head and Neck Squamous Cell Carcinoma; Hematopoietic; Human; IL18 gene; Immune; Immune system; In Vitro; Infiltration; Inflammasome; Inflammation; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-10; Lead; Link; MAP Kinase Gene; Malignant Neoplasms; Measures; Molecular; Mucous Membrane; Mus; Mutate; Nose; Oral; Oral cavity; PIK3CG gene; Pathway interactions; Pattern recognition receptor; Peptides; Pharyngeal structure; Phosphorylation; Phosphotransferases; Physiologic pulse; Physiological; Preventive measure; Preventive screening; Production; Proliferating; 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; glycogen synthase kinase 3 beta; immunoregulation; improved; in vivo; inhibitor; innate immune sensing; neutralizing antibody; new therapeutic target; novel; prevent; recruit; sensor; transcription factor; transcriptome sequencing; tumor

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.

达科他州·莱纳茨 先天免疫感受器在头颈部鳞状细胞癌中的作用 细胞内模式识别受体AIM2在炎症相关肿瘤中的作用 目前仍不清楚。初步数据显示，口服致癌物4NQO治疗的AIM2-/-小鼠 连续作为人非小细胞肺癌实验模型显示肿瘤体积较大，干扰素γ升高 与野生型相比，引流淋巴结中γ阳性的CD4T细胞的募集情况。 全组织核糖核酸测序显示4NQO处理后干扰素γ刺激基因的丰富 AIM2-/-小鼠，进一步提示AIM2限制干扰素γ。有趣的是，去除4NQO会导致组织增强 IL10在AIM2-/-小鼠体内表达，需要体内造血细胞表达。与这些一致 发现，初步数据表明，在体外Th1不同的AIM2-/-CD4T细胞产生更多的干扰素γ和IL-10 而不是野生型对照。我们假设AIM2通过阻止CD4的转换来限制HNSCC的生长 促炎性干扰素γ产生的T细胞对免疫抑制的IL-10。为了解决这一假设，我们首先 将确定AIM2调节Th1CD4T细胞中干扰素γ和IL-10平衡的分子机制 细胞。第二，我们将确定AIM2限制HNSCC的机制和细胞贡献 体内发育。我们提出的研究将揭示分子和细胞机制 AIM2和炎症推动HNSCC，这可能识别新疗法或预防的靶点 筛选，同时也定义了AIM2在形成适应性免疫中的新的生物学功能。