IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L

Immunity. 2014 May 15;40(5):772-784. doi: 10.1016/j.immuni.2014.03.010. Epub 2014 May 8.

Abstract

Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CCL20 / immunology
  • Chemokine CCL20 / metabolism
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Enzyme Activation / immunology
  • HT29 Cells
  • Histone-Lysine N-Methyltransferase
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism
  • Humans
  • Interleukins / immunology*
  • Methyltransferases / immunology*
  • Methyltransferases / metabolism
  • Mice
  • Nanog Homeobox Protein
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / immunology
  • Octamer Transcription Factor-3 / metabolism
  • Receptors, CCR6 / immunology
  • Receptors, CCR6 / metabolism
  • SOXB1 Transcription Factors / immunology
  • SOXB1 Transcription Factors / metabolism
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism

Substances

  • CCL20 protein, mouse
  • CCR6 protein, mouse
  • Chemokine CCL20
  • Homeodomain Proteins
  • Interleukins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Receptors, CCR6
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • interleukin-22