title: 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.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200001, China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Graduate Programs in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Nagarsheth
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Ende
authors.initials: E
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Owens
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin 20-081, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Zgodzinski
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin 20-081, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Majewski
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin 20-081, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wallner
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200001, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Emina
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Graduate Programs in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Tumor Biology, Univxexrsity of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|The University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000276:immunology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D019073:HT29 Cells; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000276:immunology*; D008780:Methyltransferases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000276:immunology / Q000378:metabolism; D054399:Receptors, CCR6 / Q000276:immunology / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D054418:Chemokine CCL20; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins; D007378:Interleukins; D008780:Methyltransferases; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D054399:Receptors, CCR6; D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; C486780:NANOG protein, human; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; C494086:STAT3 protein, human; C473477:DOT1L protein, human