# Cancer Cell-Intrinsic Type I Interferon Signaling Promotes Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

## TL;DR

This study shows that boosting interferon signaling in cancer cells can improve immune responses against head and neck cancer.

## Contribution

The study reveals that tumor cell-intrinsic cGAS-IFN-I signaling can convert immune-cold tumors into immune-responsive ones.

## Key findings

- MOC2 tumors lacked antigen-presenting cells and cytotoxic T cells due to suppressed cGAS-IFN-I signaling.
- Activating the cGAS-IFN-I pathway increased antigen presentation and immune cell recruitment.
- IFNB1 expression suppressed tumor growth and was enhanced by GM-CSF co-expression.

## Abstract

This study investigates the role of the tumor cell–intrinsic cGAS–IFN-I pathway in immune surveillance using mouse models of oral squamous cell carcinoma, a major subtype of head and neck squamous cell carcinoma (HNSCC). Compared to immune-responsive MOC1 tumors, immune-resistant MOC2 tumors showed suppression of this pathway and lacked antigen-presenting cells and cytotoxic T cells. MOC2-conditioned medium impaired dendritic cell differentiation and reduced MHC molecule expression. The activation of the cGAS-IFN-I pathway in MOC2 cells increased antigen presentation, induced apoptosis, and elevated chemokine expression to recruit immune cells. Expressing IFNB1 in MOC2 tumors suppressed tumor growth by attracting dendritic cells and T cells, and this effect was further amplified by co-expressing GM-CSF, which promotes immune cell development. These findings suggest that boosting tumor cell–intrinsic IFN-I signaling may enhance antitumor immunity and help control immune-cold HNSCC.

Background: The cyclic GMP-AMP synthase (cGAS)–type I interferon (IFN-I) pathway detects cytoplasmic DNA and triggers immune responses. Cancer cells often suppress this pathway to evade immune surveillance; however, its therapeutic potential remains unclear. Methods: Mouse oral squamous cell carcinoma models, representing a prominent subtype of head and neck squamous cell carcinoma (HNSCC), were employed in this study. Flow cytometry, Western blot, ELISA, and PCR were used for analysis. Results: We found that immune-unresponsive MOC2 tumors exhibited a deficiency of antigen-presenting cells and cytotoxic T lymphocytes, along with a significant suppression of the cGAS-IFN-I pathway, compared to immune-responsive MOC1 tumors. An MOC2-conditioned medium impaired the differentiation of bone marrow-derived cells into dendritic cells (DCs), reducing the expression of DC markers as well as class I and II major histocompatibility complex (MHC) molecules. The activation of the cGAS-IFN-I pathway in MOC2 cells, either through exogenous DNA or direct IFN-I expression, enhanced class I MHC expression and antigen presentation on MOC2 cells. Furthermore, IFNB1 expression in MOC2 cells induced apoptosis and upregulated chemokines, such as CXCL9 and CXCL10, which recruit immune cells. In immunocompetent mice, IFNB1 expression suppressed MOC2 tumor growth by attracting DCs and T cells, an effect amplified by co-expressing the granulocyte–macrophage colony-stimulating factor. Conclusions: These findings highlight the potential of enhancing cancer cell-intrinsic cGAS-IFN-I signaling to improve tumor immune surveillance and control the progression of immune-cold HNSCC tumors.