Unveiling the Prognostic Role of IFNAR Signaling in Neutrophils in HNC

Type I interferons (IFNs) are known for their strong anti-tumoral properties, but tumors established ways to evade interferon control, by cleaving receptors for type I IFNs (IFNAR) in tumor microenvironment, which has been demonstrated for colon cancer. Little is known about the regulation of IFNAR expression in head and neck cancer (HNC) and its effect on the immune regulation. We aimed to investigate the dynamics and effects of IFNAR loss in tumor tissue on the functionality of tumor-associated neutrophils (TANs) and its prognostic value for HNC. We evaluated IFNAR expression in tissues (tumor, normal mucosa and invasive front) of 589 patients with HNC via multicolor immunohistochemistry and its impact on the outcome. To evaluate how IFNAR degradation influences TANs activity, we used the murine model of oropharyngeal carcinoma that was injected into WT and IFNAR-deficient animals. Tumor tissue associated with poor 5 years prognosis for patients with HNC, showed significant decrease of IFNAR. Similarly in murine model, IFNAR expression was also lost on neutrophils during tumor progression. IFNAR-deficient neutrophils showed impaired anti-tumoral properties, such as cytotoxicity or T cell stimulation, while maintaining pro-tumoral functions. Preliminary data demonstrated heterogeneous expression of the IFN-regulated molecules in subpopulations of TANs in mice and humans. Unbiased computed analysis will further unveil the spatial interactions of TAN subpopulations with tumor cells and their impact on HNC prognosis.All in all, we demonstrated the relevance of interferon signaling for anti-cancer immunity and correlation of IFNAR loss with immune suppression in HNC. IFNAR expression and its downstream molecules in TANs can serve as a biomarker for HNC progression.