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

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 仍不清楚。初步数据表明，用口服致癌物 4NQO 治疗的 Aim2-/- 小鼠 作为 HNSCC 的实验模型，持续显示出更大的肿瘤、增强的 IFNγ 和增加的 与野生型对应物相比，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 限制 IFNγ。有趣的是，去除 4NQO 会导致组织增强 Il10在Aim2-/-小鼠中，需要体内AIM2的造血表达。符合这些 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 比野生型对照。我们假设 AIM2 通过阻止 CD4 的转换来限制 HNSCC 的生长 T 细胞产生促炎性 IFNγ 和免疫抑制性 IL-10。为了解决这个假设，首先我们 将确定 AIM2 调节 Th1 CD4 T 中 IFNγ 和 IL-10 平衡的分子机制 细胞。其次，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 和炎症驱动 HNSCC，这可以确定新治疗或预防的靶点 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。

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.