RT Journal Article
SR Electronic
T1 Immunomodulatory Role of Keratin 76 in Oral and Gastric Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 305961
DO 10.1101/305961
A1 Inês Sequeira
A1 Joana F. Neves
A1 Dido Carrero
A1 Qi Peng
A1 Natalia Palasz
A1 Kifayathullah Liakath-Ali
A1 Graham M. Lord
A1 Peter R. Morgan
A1 Giovanna Lombardi
A1 Fiona M. Watt
YR 2018
UL http://biorxiv.org/content/early/2018/04/21/305961.abstract
AB 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 (OSCC) 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, while their effector T cells are less proliferative than controls. Loss of Krt76 increases carcinogen-induced tumours in tongue and squamous stomach. Carcinogenesis is further increased when Treg levels are elevated experimentally. The carcinogenesis response includes upregulation of pro-inflammatory cytokines and enhanced accumulation of Tregs in the tumour microenvironment. Tregs also accumulate in human OSCC exhibiting Krt76 loss. Our study highlights the role of epithelial cells in modulating carcinogenesis via communication with cells of the immune system.