Skip to main content
Top
Published in: Cancer Immunology, Immunotherapy 11/2011

01-11-2011 | Original Article

Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin

Authors: Hui Li, Hua Zhao, Jinpu Yu, Yanjun Su, Shui Cao, Xiumei An, Xiubao Ren

Published in: Cancer Immunology, Immunotherapy | Issue 11/2011

Login to get access

Abstract

Expansion of CD4+CD25+ regulatory T cells (Tregs) in tumor microenvironment was one of the mechanisms by which cancer cells escaped host defense. Thymic stromal lymphopoietin (TSLP) contributes to the generation of natural Tregs in thymus. Therefore, the purpose of this report was to investigate the role of TSLP in the increasing prevalence of Tregs in lung cancer microenvironment. The expression ratio of TSLP protein in tumor tissues was significantly increased compared with that in benign lesion and non-cancer lung tissue. The prevalence of Tregs in tumor microenvironment was correlated with the expression of TSLP in lung cancer. Dendritic cells (DCs) were induced from peripheral blood mononuclear cells (PBMCs) collected from lung cancer patients and left unstimulated (imDCs) or exposed to hTSLP (TSLP-DCs) or LPS (LPS-DCs). TSLP-DCs expressed intermediate levels of CD83 and high levels of CD86, CD11C, and HLA-DR, which showed a characteristic of less mature DCs. TSLP-DCs secreted low levels of IL-6, IL-12, IL-10, TNF-α and IFN-γ, and high levels of TGF-β and MDC. The percentage of Tregs in CD4+CD25− T cells cocultured with TSLP-DCs group was statistically higher than that of LPS-DCs and imDCs. Transwell assays showed that TSLP-DCs exhibited increased ability to attract the migration of CD4+CD25− Tregs, when compared with imDCs. These results indicated that TSLP proteins were expressed in lung tumor tissue and correlated with the prevalence of Tregs. TSLP-DCs could induce CD4+CD25− T cells to differentiate into CD4+CD25+foxp3+ T cells and the migration of CD4+CD25+ T cells.
Literature
1.
go back to reference Ohara M, Yamaguchi Y, Matsuura KM et al (2009) Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 58(3):441–447 Ohara M, Yamaguchi Y, Matsuura KM et al (2009) Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 58(3):441–447
2.
go back to reference Li L, Chao QG, Ping LZ et al (2009) The prevalence of FOXP3+ regulatory T-cells in peripheral blood of patients with NSCLC. Cancer Biother Radiopharm 24(3):357–367PubMedCrossRef Li L, Chao QG, Ping LZ et al (2009) The prevalence of FOXP3+ regulatory T-cells in peripheral blood of patients with NSCLC. Cancer Biother Radiopharm 24(3):357–367PubMedCrossRef
3.
go back to reference Tokuno K, Hazama S, Yoshino S et al (2009) Increased prevalence of regulatory T-cells in the peripheral blood of patients with gastrointestinal cancer. Anticancer Res 29(5):1527–1532PubMed Tokuno K, Hazama S, Yoshino S et al (2009) Increased prevalence of regulatory T-cells in the peripheral blood of patients with gastrointestinal cancer. Anticancer Res 29(5):1527–1532PubMed
4.
go back to reference Strauss L, Bergmann C, Szczepanski M et al (2007) A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clin Cancer Res 13(15):4345–4354 Strauss L, Bergmann C, Szczepanski M et al (2007) A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clin Cancer Res 13(15):4345–4354
5.
go back to reference Daniel J, Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11:119–130CrossRef Daniel J, Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11:119–130CrossRef
6.
go back to reference Liu VC, Wong LY, Jang T et al (2007) Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178(5):2883–2892PubMed Liu VC, Wong LY, Jang T et al (2007) Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178(5):2883–2892PubMed
7.
go back to reference Banerjee DK, Dhodapkar MV, Matayeva E et al (2006) Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 108(8):2655–2661PubMedCrossRef Banerjee DK, Dhodapkar MV, Matayeva E et al (2006) Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 108(8):2655–2661PubMedCrossRef
8.
go back to reference Watanabe N, Wang YH, Lee HK et al (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181–1185PubMedCrossRef Watanabe N, Wang YH, Lee HK et al (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181–1185PubMedCrossRef
9.
go back to reference Lee JY, Lim YM, Park MJ et al (2008) Murine thymic stromal lymphopoietin promotes the differentiation of regulatory T cells from thymic CD4(+)CD8(−)CD25(−) naive cells in a dendritic cell-independent manner. Immunol Cell Biol 86:206–213 Lee JY, Lim YM, Park MJ et al (2008) Murine thymic stromal lymphopoietin promotes the differentiation of regulatory T cells from thymic CD4(+)CD8(−)CD25(−) naive cells in a dendritic cell-independent manner. Immunol Cell Biol 86:206–213
10.
go back to reference Ito T, Wang YH, Duramad O et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202(9):1213–1223 Ito T, Wang YH, Duramad O et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202(9):1213–1223
11.
go back to reference Vosshenrich CA, Cumano A, Müller W et al (2004) Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc Natl Acad Sci USA 101:11070–11075PubMedCrossRef Vosshenrich CA, Cumano A, Müller W et al (2004) Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc Natl Acad Sci USA 101:11070–11075PubMedCrossRef
12.
go back to reference Ramalingam TR, Pesce JT, Mentink-Kane MM et al (2009) Regulation of helminth-induced Th2 responses by thymic stromal lymphopoietin. J Immunol 182(10):6452–6459PubMedCrossRef Ramalingam TR, Pesce JT, Mentink-Kane MM et al (2009) Regulation of helminth-induced Th2 responses by thymic stromal lymphopoietin. J Immunol 182(10):6452–6459PubMedCrossRef
13.
go back to reference Li YL, Li HJ, Ji F et al (2010) Thymic stromal lymphopoietin promotes lung inflammation through activation of dendritic cells. J Asthma 47(2):117–123PubMedCrossRef Li YL, Li HJ, Ji F et al (2010) Thymic stromal lymphopoietin promotes lung inflammation through activation of dendritic cells. J Asthma 47(2):117–123PubMedCrossRef
14.
go back to reference Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680PubMedCrossRef Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680PubMedCrossRef
15.
go back to reference Liu YJ, Soumelis V, Watanabe N et al (2007) TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol 25:193–219 Liu YJ, Soumelis V, Watanabe N et al (2007) TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol 25:193–219
16.
go back to reference Fan H, Wang J, Zhou X et al (2009) Induction of antigen-specific immune tolerance by TGF-beta induced CD4+foxp3+ regulatory T cells. Int J Clin Exp Med 2(3):212–220PubMed Fan H, Wang J, Zhou X et al (2009) Induction of antigen-specific immune tolerance by TGF-beta induced CD4+foxp3+ regulatory T cells. Int J Clin Exp Med 2(3):212–220PubMed
17.
go back to reference Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809PubMedCrossRef Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809PubMedCrossRef
18.
go back to reference Adach A, Ellert-Miklaszewska A, Kaminska B (2009) Molecular characterization of STAT signaling in inflammation and tumorigenesis. Methods Mol Biol 512:265–278PubMedCrossRef Adach A, Ellert-Miklaszewska A, Kaminska B (2009) Molecular characterization of STAT signaling in inflammation and tumorigenesis. Methods Mol Biol 512:265–278PubMedCrossRef
19.
go back to reference Bensinger SJ, Walsh PT, Zhang J et al (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172(9):5287–5296PubMed Bensinger SJ, Walsh PT, Zhang J et al (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172(9):5287–5296PubMed
20.
go back to reference Hanabuchi S, Ito T, Park WR et al (2010) Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol 184(6):2999–3007PubMedCrossRef Hanabuchi S, Ito T, Park WR et al (2010) Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol 184(6):2999–3007PubMedCrossRef
21.
go back to reference Gobert M, Treilleux I, Bendriss-Vermare N et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69(5):2000–2009PubMedCrossRef Gobert M, Treilleux I, Bendriss-Vermare N et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69(5):2000–2009PubMedCrossRef
22.
go back to reference Qin XJ, Shi HZ, Deng JM et al (2009) CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clin Cancer Res 15(7):2231–2237PubMedCrossRef Qin XJ, Shi HZ, Deng JM et al (2009) CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clin Cancer Res 15(7):2231–2237PubMedCrossRef
Metadata
Title
Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin
Authors
Hui Li
Hua Zhao
Jinpu Yu
Yanjun Su
Shui Cao
Xiumei An
Xiubao Ren
Publication date
01-11-2011
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 11/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-1059-6

Other articles of this Issue 11/2011

Cancer Immunology, Immunotherapy 11/2011 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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