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Updated: Jun 11, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Impact of AIM2 on HNSCC Development
Abstract:
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 to WT mice, 4NQO-treated Aim2 -/- mice exhibited larger tumor sizes and increased tissue dysplasia. 4NQO-treated wild type 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 AIM2 restricts IFNγ. In line with this, RNA-sequencing of total tongue RNA from 4NQO-treated mice revealed Aim2 -/- mice had enhanced expression of genes related to the MHC protein complex, cell killing, and T cell activation compared to wild type mice. In addition, we observed increased macrophage infiltration into the tongue epithelium of 4NQO-treated Aim2 -/- mice. Lastly, using Aim2 -/- / Rag1 -/- -double deficient animals, we found that the adaptive immune compartment was necessary for the enhanced tumorigenesis during AIM2 deficiency. Taken together, these findings suggest AIM2 limits the progression of oral tumor development partially through regulating IFNγ and adaptive immune responses.
Insights
The cytosolic sensor Absent in Melanoma 2 (AIM2) restricts head and neck squamous cell carcinoma (HNSCC) progression. AIM2 deficiency enhances oral tumor development by promoting IFNγ and adaptive immune responses.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer often linked to chronic inflammation and immune suppression.
- The precise mechanisms underlying HNSCC development and immune evasion are not fully understood.
- Absent in Melanoma 2 (AIM2) is a cytosolic sensor with known roles in inflammasome activation and tumor suppression.
Purpose of the Study:
- To investigate the role of AIM2 in the development and progression of HNSCC.
- To elucidate the molecular mechanisms by which AIM2 influences the tumor microenvironment and immune response in HNSCC.
Main Methods:
- Utilized a 4-nitroquinoline-N-oxide (4NQO)-induced HNSCC mouse model in wild-type (WT) and Aim2-deficient (Aim2-/-) mice.
- Analyzed tumor size, tissue dysplasia, gene expression (including cytokines and immune markers), and immune cell infiltration via RNA-sequencing and immunohistochemistry.
- Employed Aim2/Rag1-double deficient mice to assess the necessity of the adaptive immune compartment.
Main Results:
- Aim2-/- mice exhibited larger HNSCC tumors and increased dysplasia compared to WT mice.
- AIM2 deficiency led to elevated expression of Interferon-gamma (IFNγ) and Irf1, suggesting AIM2 restricts IFNγ production.
- RNA-sequencing revealed enhanced expression of MHC-related genes, cell killing, and T cell activation markers in Aim2-/- mice, alongside increased macrophage infiltration.
- Tumorigenesis was exacerbated in AIM2-deficient mice, and this effect was dependent on the adaptive immune compartment.
Conclusions:
- AIM2 plays a critical role in restricting oral tumor development in HNSCC.
- AIM2 appears to limit HNSCC progression by regulating IFNγ production and adaptive immune responses.
- These findings highlight AIM2 as a potential therapeutic target for HNSCC.
