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Immunomodulatory role of Keratin 76 in oral and gastric cancer

Author

Listed:
  • Inês Sequeira

    (King’s College London, Guy’s Hospital)

  • Joana F. Neves

    (King’s College London, Guy’s Hospital)

  • Dido Carrero

    (King’s College London, Guy’s Hospital)

  • Qi Peng

    (King’s College London, Guy’s Hospital)

  • Natalia Palasz

    (King’s College London, Guy’s Hospital)

  • Kifayathullah Liakath-Ali

    (King’s College London, Guy’s Hospital
    Stanford University Medical School)

  • Graham M. Lord

    (King’s College London, Guy’s Hospital)

  • Peter R. Morgan

    (King’s College London, Guy’s Hospital)

  • Giovanna Lombardi

    (King’s College London, Guy’s Hospital)

  • Fiona M. Watt

    (King’s College London, Guy’s Hospital)

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.

Suggested Citation

  • Inês Sequeira & Joana F. Neves & Dido Carrero & Qi Peng & Natalia Palasz & Kifayathullah Liakath-Ali & Graham M. Lord & Peter R. Morgan & Giovanna Lombardi & Fiona M. Watt, 2018. "Immunomodulatory role of Keratin 76 in oral and gastric cancer," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05872-4
    DOI: 10.1038/s41467-018-05872-4
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    Cited by:

    1. Peidian Shi & Wenjie Chen & Xinxing Lyu & Zhenzhen Wang & Wenchao Li & Fengming Jia & Chunzhi Zheng & Tingting Liu & Chuan Wang & Yuan Zhang & Zihao Mi & Yonghu Sun & Xuechao Chen & Shengli Chen & Gui, 2024. "Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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