期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05872-4
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资金
- Wellcome Trust [206439/Z/17/Z]
- UK Medical Research Council [MR/PO18823/1, MR/M003493/1]
- Cancer Research UK [C219/A23522]
- RCUK/UKRI Rutherford Fund fellowship [MR/R024812/1]
- Wellcome Trust (Seed Award in Science) [204394/Z/16/Z]
- European Union (Marie Skolodowska-Curie individual fellowship)
- Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award
- Wellcome Trust [204394/Z/16/Z] Funding Source: Wellcome Trust
- BBSRC [BB/L010356/1] Funding Source: UKRI
- MRC [MR/N006445/1, MR/R024812/1, G0802068] Funding Source: UKRI
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.
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