Impact of absent in melanoma 2 on head and neck squamous cell carcinoma development

Head and neck squamous cell carcinoma (HNSCC) constitutes 90% of head and neck cancers. HNSCC development is linked to chronic inflammation, while established HNSCC tumors are often immune suppressive. However, both occur through mechanisms that are not fully understood. The cytosolic double-stranded DNA sensor absent in melanoma 2 (AIM2) is an inflammasome-forming protein that also has inflammasome-distinct roles in restricting tumorigenesis by limited PI3K signaling. Here, we used an experimental mouse model of HNSCC, involving treatment of wild-type (WT) and Aim2-/- mice with the carcinogen 4NQO in drinking water. Compared with WT mice, 4NQO-treated Aim2-/- mice exhibited larger tumors and increased tissue dysplasia. 4NQO-treated WT and Aim2-/- mice displayed similar tongue Il6, Tnf, Il1b, Il12, and Il10 expression and no consistent differences in PI3K or inflammasome activation, suggesting AIM2 may not regulate these factors during HNSCC. Instead, Ifng and Irf1 was elevated in 4NQO-treated Aim2-/- mice, suggesting that AIM2 restricts IFN-γ. In line with this, RNA sequencing of total tongue RNA from 4NQO-treated mice revealed that Aim2-/- mice had enhanced expression of genes related to the major histocompatibility complex protein complex, cell killing, and T cell activation compared with WT mice. We also observed increased macrophage infiltration into the tongue epithelium of 4NQO-treated Aim2-/- mice and an increased M1:M2 macrophage ratio. Using Aim2-/-/Rag1-/- double-deficient animals, we found that the adaptive immune compartment was necessary for the enhanced tumorigenesis during AIM2 deficiency. These findings suggest that AIM2 limits the progression of oral tumor development partially through regulating IFN-γ and adaptive immune responses.