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

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 <i>CASP8</i> are frequently found in human OSCC their role in the disease is unknown. To investigate this, we deleted <i>Casp8</i> 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 <i>Casp8</i> deletion. Oral <i>Casp8</i> deletion led to activation of autophagy. Inhibition of autophagy partially rescued epithelial integrity in <i>Casp8</i>^-/- 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 <i>Casp8</i>^-/- 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.