Caspase-8-dependent autophagy regulates neutrophil infiltration in oral squamous cell carcinoma

Menée à l'aide de modèles murins de carcinome épidermoïde de la cavité buccale, cette étude met en évidence un mécanisme par lequel l'autophagie dépendante de la caspase 8 régule l'infiltration des neutrophiles dans la tumeur

Résumé en anglais

Oral squamous cell carcinoma is genetically heterogeneous and has a poor 5-y survival rate. To explore the role of inactivating mutations in Caspase-8, we deleted the gene in the oral cavity of mice. This resulted in an epithelial barrier defect and neutrophil infiltrate, both of which were linked to the induction of autophagy in epithelial cells. On treatment with a chemical carcinogen deletion of Caspase-8 resulted in increased reactive oxygen species and tumor susceptibility. Ablation of neutrophils reduced tumor formation. Our results shed light on the functional significance of Caspase-8 in oral cancer. Oral squamous cell carcinoma (OSCC) is a subtype of head and neck cancer that arises in the multilayered epithelia of the mouth and lips. Although inactivating mutations in CASP8 are frequently found in human OSCC their role in the disease is unknown. To investigate this, we deleted Casp8 in the oral epithelium of adult mice. Loss of Caspase-8 resulted in defects in the tongue epithelial barrier and triggered a neutrophil-rich immune infiltrate distinct from that observed on epidermal Casp8 deletion. Oral Casp8 deletion led to activation of autophagy. Inhibition of autophagy partially rescued epithelial integrity in Casp8−/− mice, while induction of autophagy in wild type mice resulted in oral barrier defects and excessive neutrophil infiltration. On treatment with the carcinogen 4-nitroquinoline-1-oxide Casp8−/− mice showed increased susceptibility to developing oral tumors. Depletion of neutrophils reduced tumor incidence, which correlated with a reduction in reactive oxygen species and decreased epithelial DNA damage. Our findings establish a functional link between epithelial integrity, autophagy, and the tumor immune microenvironment, placing Caspase-8 at the center of these processes.