Elevated level of interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3.
IL-35 is a novel heterodimeric and inhibitory cytokine, composed of interleukin-12 subunit alpha (P35) and Epstein-Barr virus -induced gene 3 (EBI3). IL-35 has been reported to be produced by a range of cell types, especially regulatory T cells, and to exert immunosuppressive effects via the STATx signaling pathway. In this study, we demonstrated that IL-35 expression was elevated in both serum and tumors in patients with colorectal cancer. IL-35 mainly expressed in CD4+ T cells in human colorectal cancer tumors and adjacent tissues. Increased IL-35 expression in tumor-adjacent tissues was significantly associated with tumor metastasis. IL-35 inhibited the proliferation of CD4+CD25- T effector cells in vitro in a dose-dependent manner, and its suppression was partially reversed by applying IL-35-neutralizing antibodies. IL-35 treatment activated the phosphorylation of both STAT1 and STAT3 in human CD4+ T cells. Meanwhile, IL-35 induced a positive feedback loop to promote its own production. We observed that Tregs obtained from colorectal cancer patients were capable of inducing more IL-35 production. In addition, EBI3 promoter-driven luciferase activity was higher than that of the mock plasmid after IL-35stimulation. Thus, our study indicates that the high level of IL-35 in colorectal cancer promotes the production of IL-35 via STAT1 and STAT3, which suppresses T cell proliferation and may participate in tumor immunotolerance.
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Yanhui
Y
Ma
Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Lei
L
Chen
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Guohua
G
Xie
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Yunlan
Y
Zhou
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Chaoyan
C
Yue
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Xiangliang
X
Yuan
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Yingxia
Y
Zheng
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Weiwei
W
Wang
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Lin
L
Deng
Department of Laboratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Lisong
L
Shen
D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation
C097732:EBI3 protein, human; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C532417:interleukin-35, human
STAT1; STAT3; colorectal cancer; interleukin-35
Cancer Immun. 2007 Mar 28;7:7
17388261
Cytokine. 2015 Oct;75(2):249-55
25796985
Chin J Cancer Res. 2015 Feb;27(1):1
25717219
J Allergy Clin Immunol. 2012 Jan;129(1):207-15.e1-5
21906794
Clin Immunol. 2011 Apr;139(1):1-5
21285006
J Dig Dis. 2015 Jan;16(1):1-6
25476593
Nat Immunol. 2012 Feb 05;13(3):290-9
22306691
J Immunol Res. 2015;2015:547697
25984539
Nat Immunol. 2010 Dec;11(12):1093-101
20953201
J Immunol. 2005 Mar 1;174(5):2814-24
15728491
PLoS One. 2012;7(3):e33628
22438968
Nat Med. 2014 Jun;20(6):633-41
24743305
Nature. 2007 Nov 22;450(7169):566-9
18033300
Nature. 2014 Mar 20;507(7492):366-70
24572363
Eur J Immunol. 2010 Feb;40(2):321-9
19950173
Front Immunol. 2013 Oct 18;4:315
24151492
Cell. 2011 Mar 4;144(5):646-74
21376230
Eur J Immunol. 2008 May;38(5):1204-14
18412165
Clin Immunol. 2015 Dec;161(2):89-95
26342538
J Immunol. 2013 Mar 1;190(5):2415-23
23345334
PLoS One. 2014 Oct 30;9(10):e110126
25356878
Nat Immunol. 2012 Jul 19;13(8):722-8
22814351
Br J Cancer. 2008 Dec 2;99(11):1867-73
18985040
Annu Rev Immunol. 2007;25:221-42
17291186
Lancet. 2005 Jan 8-14;365(9454):153-65
15639298
Rheumatology (Oxford). 2015 Aug;54(8):1498-506
25731770
Cytokine Growth Factor Rev. 2015 Oct;26(5):587-93
26279360
J Biol Chem. 2015 Jul 31;290(31):19307-18
26085094
Gut. 2008 Jun;57(6):772-9
17965063
CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29
25559415
Hum Immunol. 2014 Jan;75(1):29-33
24121041
Immunity. 2003 Nov;19(5):641-4
14614851
Chin J Cancer. 2015 Sep 14;34(11):502-7
26370301
PLoS One. 2015 Jun 04;10(6):e0128219
26042836
J Immunol. 2011 Jul 1;187(1):462-71
21613618
Immunol Rev. 2001 Aug;182:18-32
11722621
Eur J Immunol. 2007 Nov;37(11):3021-9
17874423
Annu Rev Immunol. 1998;16:495-521
9597139
Immunol Rev. 2006 Aug;212:60-73
16903906