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Nat Commun. 2018 Aug 24;9(1):3437. doi: 10.1038/s41467-018-05872-4.

Immunomodulatory role of Keratin 76 in oral and gastric cancer.

Author information

1
Centre for Stem Cells & Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
2
Department of Experimental Immunobiology, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
3
Immunoregulation Laboratory, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
4
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, 265 Campus Drive, CA, 94305-5453, USA.
5
Department of Mucosal and Salivary Biology, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
6
Centre for Stem Cells & Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. Fiona.Watt@kcl.ac.uk.

Abstract

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.

PMID:
30143634
PMCID:
PMC6109110
DOI:
10.1038/s41467-018-05872-4
[Indexed for MEDLINE]
Free PMC Article

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