Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma

PLoS One. 2013 May 7;8(5):e62154. doi: 10.1371/journal.pone.0062154. Print 2013.


Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-γ producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD3 Complex / metabolism
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Squamous Cell / etiology
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Count
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Immunocompetence / immunology
  • Interleukins / pharmacology
  • Organ Transplantation / adverse effects*
  • Phosphoproteins / metabolism
  • Receptors, Interleukin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Skin / cytology
  • Skin / immunology
  • Skin / pathology
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / cytology
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology


  • CD3 Complex
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukins
  • Phosphoproteins
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • interleukin-22 receptor
  • interleukin-22