Harnessing Targeted Type I Interferon Signaling for Control of HNSCC

Objectives: Head and neck squamous cell carcinoma (HNSCC) treatment options, including surgery, chemotherapy, and radiotherapy, often cause significant morbidity. Although immune checkpoint blockade (ICB) has revolutionized HNSCC therapy by activating antitumor immunity, over 80% of patients remain unresponsive, regardless of HPV status, primarily due to insufficient antitumor T cell presence in tumors. This study aims to explore the compromised immune responses in tumors by enhancing cancer cell-intrinsic cyclic GMP-AMP synthase (cGAS)-type I interferon (IFN-I) signaling and improving dendritic cell (DC) functionality to promote tumor immune surveillance.
Methods: We employed mouse models of HNSCC, comparing inflamed, ICB-sensitive MOC1 tumors with immune-cold, ICB-resistant MOC2 tumors to investigate differences in the cGAS-IFN-I pathway. The effects of MOC2-conditioned medium on bone marrow-derived DCs were analyzed, alongside experiments introducing exogenous IFN-I and granulocyte-macrophage colony-stimulating factor (GM-CSF) to MOC2 cells. Tumor growth, DCs and CD8+ T cell infiltration were monitored to assess the impact of restoring cGAS-IFN-I signaling. MOC2 cell-induced DC differentiation and antigen presentation were investigated in vitro.
Results: MOC2 tumors exhibited significant suppression of the cGAS-IFN-I pathway compared to MOC1 tumors in C57BL/6 mouse models. MOC2-conditioned medium impaired the differentiation of bone marrow cells into functional DCs, leading to reduced antigen presentation capacity. Co-expressing IFN-I and GM-CSF in MOC2 cells successfully promoted intratumoral DC accumulation, improved antigen presentation, elicited a robust CD8+ T cell response, and inhibited tumor growth.
Conclusions: Our findings suggest that the dysfunction of cancer cell-intrinsic cGAS-IFN-I signaling in HNSCC contributes to impaired antigen-presenting DC functions and subsequent failure of antitumor T cell responses. Enhancing IFN-I signaling within cancer cells, in combination with boosting DC functionality, represents a promising therapeutic strategy for improving immune responses and controlling tumor progression in ICB-refractory HNSCC.