Home LiteratureArticle Details
PMID: 24816404 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

Immunity ·Vol. 40 ·No. 5 ·2014-05-15 ·Pages 785-800

Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, Wang Z, Wang C, Zhang Z, Xia W, Chen Z, Wang K, Zhang T, Xu J, Han Y, Zhang T, Wu X, Wang J, Gong W, Zheng S, Qiu F, Yan J, Huang J

Abstract

Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

MeSH Terms
Cell Proliferation Colorectal Neoplasms/immunology Dendritic Cells/immunology Granulocyte-Macrophage Colony-Stimulating Factor/metabolism Humans Inflammation/immunology Interleukin-17/immunology Interleukin-8/metabolism Lymphocyte Activation/immunology Myeloid Cells/immunology Receptors, Antigen, T-Cell, gamma-delta/immunology Th17 Cells/immunology Tumor Necrosis Factor-alpha/metabolism
Chemicals
IL17A protein, human Interleukin-17 Interleukin-8 Receptors, Antigen, T-Cell, gamma-delta Tumor Necrosis Factor-alpha Granulocyte-Macrophage Colony-Stimulating Factor
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Wu Pin
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wu Dang
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Ni Chao
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Ye Jun
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Chen Wuzhen
Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Hu Guoming
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wang Zhen
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wang Changrong
Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Zhang Zhigang
Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Xia Wenjie
Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Chen Zhigang
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wang Ke
Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Zhang Tao
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Xu Jinghong
Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Han Yuehua
Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Zhang Ting
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wu Xianguo
Department of Clinical Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wang Jianwei
Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Gong Weihua
Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Zheng Shu
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Qiu Fuming
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Yan Jun
Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. Electronic address: jun.yan@louisville.edu.
Huang Jian
Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China. Electronic address: drhuangjian@zju.edu.cn.
References (38)
38 references, click to expand
  1. IL-23 promotes tumour incidence and growth.
    Nature. 2006 Jul 27;442(7101):461-5 PMID: 16688182
  2. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.
    Immunity. 2011 Oct 28;35(4):596-610 PMID: 21982596
  3. High-mobility group box 1 (HMGB1)-Toll-like receptor (TLR)4-interleukin (IL)-23-IL-17A axis in drug-induced damage-associated lethal hepatitis: Interaction of γδ T cells with macrophages.
    Hepatology. 2013 Jan;57(1):373-84 PMID: 22821628
  4. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice.
    J Clin Invest. 2012 Jun;122(6):2252-6 PMID: 22546855
  5. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
    Nature. 2012 Nov 8;491(7423):254-8 PMID: 23034650
  6. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis.
    Arthritis Rheum. 2012 May;64(5):1420-9 PMID: 22144400
  7. Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation.
    Immunity. 2013 Mar 21;38(3):541-54 PMID: 23477736
  8. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma.
    J Hepatol. 2013 Nov;59(5):1007-13 PMID: 23796475
  9. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.
    Lancet. 2010 Nov 20;376(9754):1741-50 PMID: 20970847
  10. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells.
    J Immunol. 2010 Mar 1;184(5):2281-8 PMID: 20118280
  11. T(H)17 cells in tumour immunity and immunotherapy.
    Nat Rev Immunol. 2010 Apr;10(4):248-56 PMID: 20336152
  12. T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells.
    Immunity. 2010 Nov 24;33(5):791-803 PMID: 21074460
  13. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice.
    J Clin Invest. 2009 Aug;119(8):2317-29 PMID: 19662682
  14. Immunity, inflammation, and cancer.
    Cell. 2010 Mar 19;140(6):883-99 PMID: 20303878
  15. Coordinated regulation of myeloid cells by tumours.
    Nat Rev Immunol. 2012 Mar 22;12(4):253-68 PMID: 22437938
  16. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.
    Immunity. 2010 Sep 24;33(3):351-63 PMID: 20832339
  17. Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis.
    Eur J Immunol. 2010 Jul;40(7):1927-37 PMID: 20397212
  18. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.
    Immunity. 2009 Aug 21;31(2):331-41 PMID: 19682929
  19. Differentiation, phenotype, and function of interleukin-17-producing human Vγ9Vδ2 T cells.
    Blood. 2011 Jul 7;118(1):129-38 PMID: 21505189
  20. Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans.
    Blood. 2009 Jun 25;113(26):6611-8 PMID: 19395673
  21. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing gammadelta T cells.
    Eur J Immunol. 2010 Jul;40(7):1873-6 PMID: 20549671
  22. Cancer-related inflammation.
    Nature. 2008 Jul 24;454(7203):436-44 PMID: 18650914
  23. Inflammation and cancer: back to Virchow?
    Lancet. 2001 Feb 17;357(9255):539-45 PMID: 11229684
  24. Human inflammatory dendritic cells induce Th17 cell differentiation.
    Immunity. 2013 Feb 21;38(2):336-48 PMID: 23352235
  25. Interactions between the microbiota and the immune system.
    Science. 2012 Jun 8;336(6086):1268-73 PMID: 22674334
  26. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer.
    Cancer Res. 2011 Feb 15;71(4):1263-71 PMID: 21303976
  27. Inflammation and cancer.
    Nature. 2002 Dec 19-26;420(6917):860-7 PMID: 12490959
  28. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.
    Cancer Cell. 2005 Mar;7(3):211-7 PMID: 15766659
  29. Epithelial tight junctional changes in colorectal cancer tissues.
    ScientificWorldJournal. 2011 Apr 05;11:826-41 PMID: 21479352
  30. Nuclear factor-kappaB in cancer development and progression.
    Nature. 2006 May 25;441(7092):431-6 PMID: 16724054
  31. TNF signaling drives myeloid-derived suppressor cell accumulation.
    J Clin Invest. 2012 Nov;122(11):4094-104 PMID: 23064360
  32. Six-of-the-best: unique contributions of γδ T cells to immunology.
    Nat Rev Immunol. 2013 Feb;13(2):88-100 PMID: 23348415
  33. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses.
    Nat Med. 2009 Sep;15(9):1016-22 PMID: 19701202
  34. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy.
    Nat Med. 2013 Sep;19(9):1114-23 PMID: 23913124
  35. The genomic landscapes of human breast and colorectal cancers.
    Science. 2007 Nov 16;318(5853):1108-13 PMID: 17932254
  36. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.
    Nat Med. 2009 Aug;15(8):946-50 PMID: 19648929
  37. Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.
    Cancer Res. 2005 Jan 1;65(1):166-76 PMID: 15665292
  38. Deficiency in IL-17-committed Vγ4(+) γδ T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis.
    Nat Immunol. 2013 Jun;14(6):584-92 PMID: 23624556
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2014.03.013
Email
jun.yan@louisville.edu
drhuangjian@zju.edu.cn
Published
2014-05-15
Epub
2014-00-08
Pages
785-800
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC4716654
Subset
IM
Grants
NCI NIH HHS · P01 CA163223 · United States
NCI NIH HHS · R01 CA150947 · United States
NCI NIH HHS · R01CA150947 · United States
NCI NIH HHS · P01CA163223, · United States
External Links
PubMed source DOI: 10.1016/j.immuni.2014.03.013 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2