NK Cell and Fibroblast-Mediated Regulation of Skin Squamous Cell Carcinoma Invasion by CLEC2A Is Compromised in Xeroderma Pigmentosum

J Invest Dermatol. 2020 Sep;140(9):1723-1732. doi: 10.1016/j.jid.2020.01.021. Epub 2020 Feb 13.


The ability of cancer cells to invade and disseminate can be affected by components of the surrounding microenvironment. To identify dermal components that regulate the growth of epidermal carcinomas, we studied the genetic disease called xeroderma pigmentosum that bears mutations in genes involved in the nucleotide excision repair of DNA. Patients with xeroderma pigmentosum are more prone to develop cutaneous tumors than the general population and their dermal fibroblasts display the features of dermal cancer-associated fibroblasts, which promote the invasion of keratinocytes. Here, we report that 3-dimensional dermal cultures of fibroblasts from healthy donors but not from patients with xeroderma pigmentosum complementation group C express CLEC2A, which is the ligand of the activating NK cell receptor NKp65. A similar loss of CLEC2A was observed in sporadic dermal cancer-associated fibroblasts and upon the culture of fibroblasts with cutaneous squamous cell carcinoma-conditioned medium. Using an innovative 3-dimensional organotypic skin culture model that contain NK cells in addition to fibroblasts and squamous cell carcinoma cells, we unveiled a key role of CLEC2A that orchestrates a crosstalk between fibroblasts and NK cells, thereby leading to the control of squamous cell carcinoma invasion. These findings indicate that CLEC2A-expressing dermal fibroblasts play a major role in immune surveillance of the skin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biopsy
  • Cancer-Associated Fibroblasts / immunology
  • Cancer-Associated Fibroblasts / pathology*
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Cell Communication / immunology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Coculture Techniques
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunologic Surveillance
  • Infant
  • Infant, Newborn
  • Killer Cells, Natural / immunology
  • Lectins, C-Type / deficiency*
  • Male
  • Neoplasm Invasiveness / immunology
  • Neoplasm Invasiveness / pathology
  • Primary Cell Culture
  • Receptors, NK Cell Lectin-Like / metabolism
  • Skin / immunology
  • Skin / pathology
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • Tumor Microenvironment / immunology
  • Xeroderma Pigmentosum / genetics
  • Xeroderma Pigmentosum / immunology
  • Xeroderma Pigmentosum / pathology*
  • Young Adult


  • CLEC2A protein, human
  • DNA-Binding Proteins
  • KLRF2 protein, human
  • Lectins, C-Type
  • Receptors, NK Cell Lectin-Like
  • XPC protein, human

Supplementary concepts

  • Xeroderma Pigmentosum, Complementation Group C