The inability to resolve chronic inflammation is considered one of the initial triggers of carcinogenesis. Until recently, keratins were mainly regarded as cytoskeletal scaffolds; however, there is an emerging role for keratins in the regulation of epidermal immunity. Keratin 76 (Krt76) is expressed in the differentiated epithelial layers of skin, oral cavity and squamous stomach. Krt76 downregulation in human oral squamous cell carcinomas correlates with poor prognosis. We show that genetic ablation of Krt76 in mice leads to spleen and lymph node enlargement, an increase in regulatory T cells (Tregs) and high levels of pro-inflammatory cytokines. Krt76-/- Tregs have increased suppressive ability correlated with increased CD39 and CD73 expression.
The Krt76-/- mouse serves as a model to explore the link between chronic inflammation and cancer, providing an opportunity to examine the impact of aberrant epithelial differentiation and consequent chronic inflammation on tumorigenesis. We observed that loss of Krt76 increases carcinogen-induced tumours in tongue and squamous stomach. The carcinogenesis response includes upregulation of pro-inflammatory cytokines and enhanced accumulation of Tregs in the tumour microenvironment.
This study highlights the importance of keratins as immunomodulators and demonstrates their importance in tumour progression.