Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

Open Access 01-12-2020 | Colorectal Cancer | Research

Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients

Authors: Dan Wang, Weina Yu, Jingyao Lian, Qian Wu, Shasha Liu, Li Yang, Feng Li, Lan Huang, Xinfeng Chen, Zhen Zhang, Aitian Li, Jinbo Liu, Zhenqiang Sun, Junxia Wang, Weitang Yuan, Yi Zhang

Published in: Journal of Hematology & Oncology | Issue 1/2020

Login to get access

Abstract

Background

CD8+ T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8+ T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8+ T cell infiltration in CRC tissues and the role of chemokine–chemokine receptor signaling in regulation of T cell recruitment.

Methods

We screened chemokines and cytokines in healthy donor and CRC tissues from early- and advanced-stage patients using multiplex assays and PCR screening. We also utilized transcription factor activation profiling arrays and established a xenograft mouse model.

Results

Compared with tumor tissues of early-stage CRC patients, CD8+ T cell density was lower in advanced-stage tumor tissues. PCR screening showed that CXCL10 levels were significantly increased in advanced-stage tumor tissues. CXCR3 (the receptor of CXCL10) expression on CD8+ T cells was lower in the peripheral blood of advanced-stage patients. The migratory ability of CD8+ T cells to CXCL10 depended on CXCR3 expression. Multiplex arrays showed that IL-17A was increased in advanced-stage patient sera, which markedly downregulated CXCR3 expression via activating STAT3 signaling and reduced CD8+ T cell migration. Similar results were found after CD8+ T cells were treated with Th17 cell supernatant. Adding anti-IL-17A or the STAT3 inhibitor, Stattic, rescued these effects in vitro and in vivo. Moreover, survival analysis showed that patients with low CD8 and CXCR3 expression and high IL-17A levels had significantly worse prognosis.

Conclusions

CD8+ T cell infiltration in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/STAT3/CXCR3 axis. Our findings indicate that the T cell infiltration in the tumor microenvironment may be improved by inhibiting STAT3 signaling.
Appendix
Available only for authorised users
Literature
1.
Fountzilas E, Kotoula V, Tikas I, Manousou K, Papadopoulou K, Poulios C, et al. Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer. Oncotarget. 2018;9:35623–38.PubMedPubMedCentralCrossRef
2.
Nazemalhosseini-Mojarad E, Mohammadpour S, Torshizi Esafahani A, Gharib E, Larki P, Moradi A, et al. Intratumoral infiltrating lymphocytes correlate with improved survival in colorectal cancer patients: independent of oncogenetic features. J Cell Physiol. 2019;234:4768–77.PubMedCrossRef
3.
Huang CY, Chiang SF, Ke TW, Chen TW, You YS, Chen WT, et al. Clinical significance of programmed death 1 ligand-1 (CD274/PD-L1) and intra-tumoral CD8+ T-cell infiltration in stage II-III colorectal cancer. Sci Rep. 2018;8:15658.PubMedPubMedCentralCrossRef
4.
Yoon HH, Shi Q, Heying EN, Muranyi A, Bredno J, Ough F, et al. Intertumoral heterogeneity of CD3(+) and CD8(+) T-cell densities in the microenvironment of DNA mismatch-repair-deficient colon cancers: implications for prognosis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25:125–33.CrossRef
5.
Trajkovski G, Ognjenovic L, Jota G, Hadzi-Manchev D, Trajkovska V, Volcevski G, et al. Tumour lymphocytic infiltration, its structure and influence in colorectal cancer progression. Open access Macedonian journal of medical sciences. 2018;6:1003–9.PubMedPubMedCentralCrossRef
6.
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231–5.PubMedCrossRef
7.
Xue J, Yu X, Xue L, Ge X, Zhao W, Peng W. Intrinsic beta-catenin signaling suppresses CD8(+) T-cell infiltration in colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019;115:108921.CrossRef
8.
Lu C, Yang D, Klement JD, Oh IK, Savage NM, Waller JL, et al. SUV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion. Cancer immunology research. 2019;7:414–27.PubMedPubMedCentralCrossRef
9.
Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:610–8.CrossRef
10.
Villarreal DO, L'Huillier A, Armington S, Mottershead C, Filippova EV, Coder BD, et al. Targeting CCR8 induces protective antitumor immunity and enhances vaccine-induced responses in colon cancer. Cancer Res. 2018;78:5340–8.PubMedCrossRef
11.
Berinstein NL, McNamara M, Nguyen A, Egan J, Wolf GT. Increased immune infiltration and chemokine receptor expression in head and neck epithelial tumors after neoadjuvant immunotherapy with the IRX-2 regimen. Oncoimmunology. 2018;7:e1423173.PubMedPubMedCentralCrossRef
12.
Sharma RK, Chheda ZS, Jala VR, Haribabu B. Regulation of cytotoxic T-lymphocyte trafficking to tumors by chemoattractants: implications for immunotherapy. Expert review of vaccines. 2015;14:537–49.PubMedCrossRef
13.
Gordon-Alonso M, Hirsch T, Wildmann C, van der Bruggen P. Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun. 2017;8:793.PubMedPubMedCentralCrossRef
14.
Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest. 2017;127:1425–37.PubMedPubMedCentralCrossRef
15.
Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B. Chemoattractant receptors BLT1 and CXCR3 regulate antitumor immunity by facilitating CD8+ T cell migration into tumors. J Immunol. 2016;197:2016–26.PubMedCrossRef
16.
Zumwalt TJ, Arnold M, Goel A, Boland CR. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration. Oncotarget. 2015;6:2981–91.PubMedCrossRef
17.
Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, et al. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology. 2010;138:1429–40.PubMedCrossRef
18.
Dimberg J, Skarstedt M, Lofgren S, Zar N, Matussek A. Protein expression and gene polymorphism of CXCL10 in patients with colorectal cancer. Biomedical reports. 2014;2:340–3.PubMedPubMedCentralCrossRef
19.
Toiyama Y, Fujikawa H, Kawamura M, Matsushita K, Saigusa S, Tanaka K, et al. Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer. Int J Oncol. 2012;40:560–6.PubMed
20.
Clancy-Thompson E, King LK, Nunnley LD, Mullins IM, Slingluff CL Jr, Mullins DW. Peptide vaccination in Montanide adjuvant induces and GM-CSF increases CXCR3 and cutaneous lymphocyte antigen expression by tumor antigen-specific CD8 T cells. Cancer immunology research. 2013;1:332–9.PubMedCrossRef
21.
Hu JK, Kagari T, Clingan JM, Matloubian M. Expression of chemokine receptor CXCR3 on T cells affects the balance between effector and memory CD8 T-cell generation. Proc Natl Acad Sci U S A. 2011;108:E118–27.PubMedPubMedCentralCrossRef
22.
Oghumu S, Dong R, Varikuti S, Shawler T, Kampfrath T, Terrazas CA, et al. Distinct populations of innate CD8+ T cells revealed in a CXCR3 reporter mouse. J Immunol. 2013;190:2229–40.PubMedCrossRef
23.
Ciardiello C, Leone A, Budillon A. The crosstalk between cancer stem cells and microenvironment is critical for solid tumor progression: the significant contribution of extracellular vesicles. Stem Cells Int. 2018;2018:6392198.PubMedPubMedCentralCrossRef
24.
Chen D, Xie H, Luo X, Yu X, Fu X, Gu H, et al. Roles of Th17 cells in pulmonary granulomas induced by Schistosoma japonicum in C57BL/6 mice. Cell Immunol. 2013;285:149–57.PubMedCrossRef
25.
Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.CrossRefPubMed
26.
Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012;36:362–73.PubMedCrossRef
27.
He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 2010;184:2281–8.PubMedCrossRef
28.
Ma S, Cheng Q, Cai Y, Gong H, Wu Y, Yu X, et al. IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 2014;74:1969–82.PubMedCrossRef
29.
Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206:1457–64.PubMedPubMedCentralCrossRef
30.
31.
Lu L, Pan K, Zheng HX, Li JJ, Qiu HJ, Zhao JJ, et al. IL-17A promotes immune cell recruitment in human esophageal cancers and the infiltrating dendritic cells represent a positive prognostic marker for patient survival. J Immunother. 2013;36:451–8.PubMedCrossRef
32.
Wang D, Yang L, Yu W, Wu Q, Lian J, Li F, et al. Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-kappaB signaling. Journal for immunotherapy of cancer. 2019;7:215.PubMedPubMedCentralCrossRef
33.
Li L, Yang L, Wang L, Wang F, Zhang Z, Li J, et al. Impaired T cell function in malignant pleural effusion is caused by TGF-beta derived predominantly from macrophages. Int J Cancer. 2016;139:2261–9.PubMedCrossRef
34.
Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572–9.PubMedPubMedCentralCrossRef
35.
Xie Q, Yang Z, Huang X, Zhang Z, Li J, Ju J, et al. Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway. J Hematol Oncol. 2019;12:60.PubMedPubMedCentralCrossRef
36.
Pirozyan MR, Nguyen N, Cameron B, Luciani F, Bull RA, Zekry A, et al. Chemokine-regulated recruitment of antigen-specific T-cell subpopulations to the liver in acute and chronic hepatitis C infection. J Infect Dis. 2019;219:1430–8.PubMedCrossRef
37.
Scuto A, Kujawski M, Kowolik C, Krymskaya L, Wang L, Weiss LM, et al. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. Cancer Res. 2011;71:3182–8.PubMedPubMedCentralCrossRef
38.
39.
Soong RS, Song L, Trieu J, Knoff J, He L, Tsai YC, et al. Toll-like receptor agonist imiquimod facilitates antigen-specific CD8+ T-cell accumulation in the genital tract leading to tumor control through IFNgamma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20:5456–67.CrossRef
40.
Wadwa M, Klopfleisch R, Adamczyk A, Frede A, Pastille E, Mahnke K, et al. IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites. Mucosal Immunol. 2016;9:1263–77.PubMedCrossRef
41.
Oghumu S, Terrazas CA, Varikuti S, Kimble J, Vadia S, Yu L, et al. CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015;29:1019–28.CrossRef
42.
Jiang PJ, Zhao AM, Bao SM, Xiao SJ, Xiong M. Expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4(+) T cells in CBA/JxDBA/2 mouse model, selectively induced by IL-4 and IL-10, regulates the embryo resorption rate. Chin Med J. 2009;122:1917–21.PubMed
43.
Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, et al. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy. Cancer Treat Rev. 2018;63:40–7.PubMedCrossRef
44.
Groom JR, Luster AD. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol. 2011;89:207–15.PubMedCrossRef
45.
Gao Q, Wang S, Chen X, Cheng S, Zhang Z, Li F, et al. Cancer-cell-secreted CXCL11 promoted CD8(+) T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC. Journal for immunotherapy of cancer. 2019;7:42.PubMedPubMedCentralCrossRef
46.
Maimela NR, Liu S, Zhang Y. Fates of CD8+ T cells in tumor microenvironment. Computational and structural biotechnology journal. 2019;17:1–13.PubMedCrossRef
47.
Mostafa H, Pala A, Hogel J, Hlavac M, Dietrich E, Westhoff MA, et al. Immune phenotypes predict survival in patients with glioblastoma multiforme. J Hematol Oncol. 2016;9:77.PubMedPubMedCentralCrossRef
48.
49.
Ren T, Zhu L, Cheng M. CXCL10 accelerates EMT and metastasis by MMP-2 in hepatocellular carcinoma. Am J Transl Res. 2017;9:2824–37.PubMedPubMedCentral
50.
Wendel M, Galani IE, Suri-Payer E, Cerwenka A. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res. 2008;68:8437–45.PubMedCrossRef
51.
Na H, Liu X, Li X, Zhang X, Wang Y, Wang Z, et al. Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis. J Hematol Oncol. 2017;10:28.PubMedPubMedCentralCrossRef
52.
Krzystek-Korpacka M, Diakowska D, Kapturkiewicz B, Bebenek M, Gamian A. Profiles of circulating inflammatory cytokines in colorectal cancer (CRC), high cancer risk conditions, and health are distinct. Possible implications for CRC screening and surveillance. Cancer Lett. 2013;337:107–14.PubMedCrossRef
53.
Singh UP, Singh S, Taub DD, Lillard JW Jr. Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/- mice. J Immunol. 2003;171:1401–6.PubMedCrossRef
54.
Singh UP, Singh NP, Singh B, Hofseth LJ, Taub DD, Price RL, et al. Role of resveratrol-induced CD11b(+) Gr-1(+) myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3(+) T cells and amelioration of chronic colitis in IL-10(-/-) mice. Brain Behav Immun. 2012;26:72–82.PubMedCrossRef
55.
Barbi J, Oghumu S, Lezama-Davila CM, Satoskar AR. IFN-gamma and STAT1 are required for efficient induction of CXC chemokine receptor 3 (CXCR3) on CD4+ but not CD8+ T cells. Blood. 2007;110:2215–6.PubMedPubMedCentralCrossRef
56.
Choi J, Ahn SS, Lim Y, Lee YH, Shin SY. Inhibitory effect of Alisma canaliculatum ethanolic extract on NF-kappaB-dependent CXCR3 and CXCL10 expression in TNFalpha-exposed MDA-MB-231 breast cancer cells. Int J Mol Sci. 2018;19.
57.
Yue C, Shen S, Deng J, Priceman SJ, Li W, Huang A, et al. STAT3 in CD8+ T cells inhibits their tumor accumulation by downregulating CXCR3/CXCL10 axis. Cancer immunology research. 2015;3:864–70.PubMedPubMedCentralCrossRef
58.
Kujawski M, Zhang C, Herrmann A, Reckamp K, Scuto A, Jensen M, et al. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res. 2010;70:9599–610.PubMedPubMedCentralCrossRef
59.
60.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51.PubMedCrossRef
61.
Yang H, Yamazaki T, Pietrocola F, Zhou H, Zitvogel L, Ma Y, et al. STAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating type 1 interferon production by cancer cells. Cancer Res. 2015;75:3812–22.PubMedCrossRef
62.
Li L, Yang L, Cheng S, Fan Z, Shen Z, Xue W, et al. Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity. Mol Cancer. 2019;18:108.PubMedPubMedCentralCrossRef
63.
Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C, et al. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 2011;71:6997–7009.PubMedCrossRef
64.
Zhao F, Hoechst B, Gamrekelashvili J, Ormandy LA, Voigtlander T, Wedemeyer H, et al. Human CCR4+ CCR6+ Th17 cells suppress autologous CD8+ T cell responses. J Immunol. 2012;188:6055–62.PubMedCrossRef
65.
Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, et al. IFN-gamma and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010;40:3017–27.PubMedCrossRef
66.
Streeck H, Cohen KW, Jolin JS, Brockman MA, Meier A, Power KA, et al. Rapid ex vivo isolation and long-term culture of human Th17 cells. J Immunol Methods. 2008;333:115–25.PubMedCrossRef
Metadata
Title
Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients
Authors
Dan Wang
Weina Yu
Jingyao Lian
Qian Wu
Shasha Liu
Li Yang
Feng Li
Lan Huang
Xinfeng Chen
Zhen Zhang
Aitian Li
Jinbo Liu
Zhenqiang Sun
Junxia Wang
Weitang Yuan
Yi Zhang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00897-z

Other articles of this Issue 1/2020

Journal of Hematology & Oncology 1/2020 Go to the issue

Review

Advances in the assessment of minimal residual disease in mantle cell lymphoma

Review

CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma

Rapid communication

Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia

Editorial

Anticancer drug R&D landscape in China

Research

Low high-density lipoprotein and increased risk of several cancers: 2 population-based cohort studies including 116,728 individuals

Research

The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits