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

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.

• Authors: Ilona Kryczek, Yanwei Lin, Nisha Nagarsheth, Dongjun Peng, Lili Zhao, Ende Zhao, Linda Vatan, Wojciech Szeliga, Yali Dou, Scott Owens, Witold Zgodzinski, Marek Majewski, Grzegorz Wallner, Jingyuan Fang, Emina Huang, Weiping Zou
• Journal: Immunity (Immunity) Vol. 40 Issue 5 Pg. 772-784 (May 15 2014) ISSN: 1097-4180 [Electronic] United States
• PMID: 24816405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Cell Proliferation
• Chemokine CCL20 (immunology, metabolism)
• Colorectal Neoplasms (immunology, mortality, pathology)
• Enzyme Activation (immunology)
• HT29 Cells
• Histone-Lysine N-Methyltransferase
• Homeodomain Proteins (immunology, metabolism)
• Humans
• Interleukins (immunology)
• Methyltransferases (immunology, metabolism)
• Mice
• Nanog Homeobox Protein
• Neoplasm Transplantation
• Neoplastic Stem Cells (immunology, pathology)
• Octamer Transcription Factor-3 (immunology, metabolism)
• Receptors, CCR6 (immunology, metabolism)
• SOXB1 Transcription Factors (immunology, metabolism)
• STAT3 Transcription Factor (immunology, metabolism)
• Interleukin-22