IL-22(+)CD4(+) T Cells Promote Colorectal Cancer Stemness Via STAT3 Transcription Factor Activation and Induction of the Methyltransferase DOT1L

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2014 May 13

PMID 24816405

Citations 232

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

Affiliations

Soon will be listed here.

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.

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References

Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M . Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999; 284(5413):479-82. DOI: 10.1126/science.284.5413.479. View

Kryczek I, Liu S, Roh M, Vatan L, Szeliga W, Wei S . Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer. 2011; 130(1):29-39. PMC: 3164893. DOI: 10.1002/ijc.25967. View

Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M . STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009; 206(7):1465-72. PMC: 2715097. DOI: 10.1084/jem.20082683. View

Coussens L, Zitvogel L, Palucka A . Neutralizing tumor-promoting chronic inflammation: a magic bullet?. Science. 2013; 339(6117):286-91. PMC: 3591506. DOI: 10.1126/science.1232227. View

Min J, Feng Q, Li Z, Zhang Y, Xu R . Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. 2003; 112(5):711-23. DOI: 10.1016/s0092-8674(03)00114-4. View

Li L, Shaw P . Elevated activity of STAT3C due to higher DNA binding affinity of phosphotyrosine dimer rather than covalent dimer formation. J Biol Chem. 2006; 281(44):33172-81. DOI: 10.1074/jbc.M606940200. View

Trifari S, Kaplan C, Tran E, Crellin N, Spits H . Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009; 10(8):864-71. DOI: 10.1038/ni.1770. View

Curiel T, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P . Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; 10(9):942-9. DOI: 10.1038/nm1093. View

Ben-Neriah Y, Karin M . Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol. 2011; 12(8):715-23. DOI: 10.1038/ni.2060. View

10.

Kirchberger S, Royston D, Boulard O, Thornton E, Franchini F, Szabady R . Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med. 2013; 210(5):917-31. PMC: 3646494. DOI: 10.1084/jem.20122308. View

11.

Pardoll D . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4):252-64. PMC: 4856023. DOI: 10.1038/nrc3239. View

12.

Wang Y, Liu Y, Malek S, Zheng P, Liu Y . Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011; 8(4):399-411. PMC: 3084595. DOI: 10.1016/j.stem.2011.02.006. View

13.

Cui T, Kryczek I, Zhao L, Zhao E, Kuick R, Roh M . Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity. 2013; 39(3):611-21. PMC: 3831370. DOI: 10.1016/j.immuni.2013.08.025. View

14.

Smith J, Deane N, Wu F, Merchant N, Zhang B, Jiang A . Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology. 2009; 138(3):958-68. PMC: 3388775. DOI: 10.1053/j.gastro.2009.11.005. View

15.

Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P . B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 2006; 203(4):871-81. PMC: 2118300. DOI: 10.1084/jem.20050930. View

16.

Henikoff S, Shilatifard A . Histone modification: cause or cog?. Trends Genet. 2011; 27(10):389-96. DOI: 10.1016/j.tig.2011.06.006. View

17.

Zou W, Machelon V, Borvak J, Nome F, Isaeva T, Wei S . Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med. 2001; 7(12):1339-46. DOI: 10.1038/nm1201-1339. View

18.

Zheng Y, Valdez P, Danilenko D, Hu Y, Sa S, Gong Q . Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008; 14(3):282-9. DOI: 10.1038/nm1720. View

19.

Basu R, OQuinn D, Silberger D, Schoeb T, Fouser L, Ouyang W . Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity. 2012; 37(6):1061-75. PMC: 3678257. DOI: 10.1016/j.immuni.2012.08.024. View

20.

Daigle S, Olhava E, Therkelsen C, Majer C, Sneeringer C, Song J . Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011; 20(1):53-65. PMC: 4046888. DOI: 10.1016/j.ccr.2011.06.009. View