Regulatory T Cells in Colorectal Cancer

Document Type : Review article

Authors

Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Abstract

One of the essential protection mechanisms of immune system is Treg cells which play an important role in maintenance of immune homeostasis. However, they may also inhibit immune functions against tumor cells. It has been reported that Treg cells are increased in patients suffering from different types of cancer. Increased number of Treg cells has been shown in tumor lymph nodes, peripheral blood, and tumor sites of patient with Colorectal Cancer (CRC). However, it is clear that Treg cells are increased in CRC patients, but the prognostic impact of Treg cells in CRC patients is a matter of debate. It seems that the function of these cells depend on the stage of CRC development. The aim of the present review article is to make an attempt to provide vision on the role of Treg in CRC. Finally, the potential approaches for the treatment of CRC are discussed.

Keywords


Strum WB. Colorectal adenomas. The New England Journal of Medicine. 2016; 2016(374):1065-75. [DOI:10.1056/NEJMra1513581] [PMID]
Nisar B, Faizi KS, Ali A. Different clinical presentations of patients with Colorectal Cancer.
Wang YM, Ghali J, Zhang GY, Hu M, Wang Y, Sawyer A, et al. Development and function of Foxp3+ regulatory T cells. Nephrology. 2016; 21(2):81-5. [DOI:10.1111/nep.12652] [PMID]
Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, et al. Two FOXP3+ CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nature Medicine. 2016; 22(6):679-84. [DOI:10.1038/nm.4086] [PMID]
Rampling R, Peoples S, Mulholland PJ, James A, Al Salihi O, Twelves CJ, et al. A Cancer research UK first time in human phase I trial of IMA950 (novel multi peptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clinical Cancer Research; 2016.
Sebastian M, Lopez Ocasio M, Metidji A, Rieder SA, Shevach EM, Thornton AM. Helios controls a limited subset of regulatory T cell functions. The Journal of Immunology. 2016; 196(1):144-55. [DOI:10.4049/jimmunol.1501704] [PMID] [PMCID]
Haque M, Song J, Fino K, Sandhu P, Song X, Lei F, et al. Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Scientific reports. 2016; 6. [DOI:10.1038/srep20588]
Haque M, Fino K, Lei F, Xiong X, Song J. Utilizing regulatory T cells against rheumatoid arthritis. Frontiers in oncology. 2014; 4:209. [DOI:10.3389/fonc.2014.00209] [PMID] [PMCID]
Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009; 30(6):899-911. [DOI:10.1016/j.immuni.2009.03.019] [PMID]
Seddiki N, Santner Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. The Journal of Experimental Medicine. 2006; 203(7):1693-700. [DOI:10.1084/jem.20060468] [PMID] [PMCID]
Wing K, Onishi Y, Prieto Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322(5899):271-5. [DOI:10.1126/science.1160062] [PMID]
Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, et al. Human CD25+ CD4+ T suppressor cell clones produce transforming growth factor β, but not interleukin 10, and are distinct from type 1 T regulatory cells. The Journal of experimental medicine. 2002; 196(10):1335-46. [DOI:10.1084/jem.20021139] [PMID] [PMCID]
Baecher Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. The Journal of Immunology. 2006; 176(8):4622-31. [DOI:10.4049/jimmunol.176.8.4622] [PMID]
Chevalier MF, Didier C, Petitjean G, Karmochkine M, Girard PM, Barré-Sinoussi F, et al. Phenotype Alterations in Regulatory T-Cell Subsets in Primary HIV Infection and Identification of Tr1-like Cells as the Main Interleukin 10–Producing CD4+ T Cells. Journal of Infectious Diseases. 2015; 211(5):769-79. [DOI:10.1093/infdis/jiu549] [PMID]
Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews Immunology. 2006; 6(4):295-307. [DOI:10.1038/nri1806] [PMID]
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Reviews Immunology. 2010; 10(7):490-500. [DOI:10.1038/nri2785] [PMID]
Wang Q, Feng M, Yu T, Liu X, Zhang P. Intratumoral regulatory T cells are associated with suppression of colorectal carcinoma metastasis after resection through overcoming IL-17 producing T cells. Cellular immunology. 2014; 287(2):100-5. [DOI:10.1016/j.cellimm.2014.01.002] [PMID]
Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Advances in cancer research. 2010; 107:57-117. [DOI:10.1016/S0065-230X(10)07003-X]
Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL. The frequency and suppressor function of CD4+ CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clinical Cancer Research. 2007; 13(21):6301-11. [DOI:10.1158/1078-0432.CCR-07-1403] [PMID]
Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clinical Cancer Research. 2003; 9(2):606-12. [PMID]
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine. 2004; 10(9):942-9. [DOI:10.1038/nm1093] [PMID]
Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E, et al. The expression of the regulatory T cell–specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clinical Cancer Research. 2005; 11(23):8326-31. [DOI:10.1158/1078-0432.CCR-05-1244] [PMID]
Deng L, Zhang H, Luan Y, Zhang J, Xing Q, Dong S, et al. Accumulation of foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clinical Cancer Research. 2010; 16(16):4105-12. [DOI:10.1158/1078-0432.CCR-10-1073] [PMID]
Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NEH, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clinical Cancer Research. 2006; 12(2):465-72. [DOI:10.1158/1078-0432.CCR-05-1886] [PMID]
Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008; 93(2):193-200. [DOI:10.3324/haematol.11702] [PMID]
Carreras J, Lopez Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006; 108(9):2957-64. [DOI:10.1182/blood-2006-04-018218] [PMID]
Farinha P, Al-Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD. The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood. 2010; 115(2):289-95. [DOI:10.1182/blood-2009-07-235598] [PMID]
Droeser R, Zlobec I, Kilic E, Güth U, Heberer M, Spagnoli G, et al. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers. BMC Cancer. 2012; 12(1):1. [DOI:10.1186/1471-2407-12-134] [PMID] [PMCID]
Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Seminars in cancer biology. London: Elsevier; 2012.
Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3+ regulatory T cells under inflammatory or non-inflammatory conditions. Seminars in immunology; 2011.
Whiteside T. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008; 27(45):5904-12. [DOI:10.1038/onc.2008.271] [PMID] [PMCID]
Oberg H-H, Juricke M, Kabelitz D, Wesch D. Regulation of T cell activation by TLR ligands. European Journal of Cell Biology. 2011; 90(6):582-92. [DOI:10.1016/j.ejcb.2010.11.012] [PMID]
Yoshie O, Matsushima K. CCR4 and its ligands: from bench to bedside. International Immunology. 2015; 27(1):11-20. [DOI:10.1093/intimm/dxu079] [PMID]
Ondondo BO, Gallimore A, Jones EG, Godkin A. Home sweet home: The tumor microenvironment as a haven for regulatory T cells. Frontiers in Immunology. 2013; 4:197. [DOI:10.3389/fimmu.2013.00197] [PMID] [PMCID]
Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunology, Immunotherapy. 2011; 60(7):909-18. [DOI:10.1007/s00262-011-1046-y] [PMID]
Rech AJ, Mick R, Kaplan DE, Chang K-M, Domchek SM, Vonderheide RH. Homeostasis of peripheral FoxP3+ CD4+ regulatory T cells in patients with early and late stage breast cancer. Cancer Immunology, Immunotherapy. 2010; 59(4):599-607. [DOI:10.1007/s00262-009-0780-x] [PMID]
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. Journal of Clinical Oncology. 2009; 27(2):186-92. [DOI:10.1200/JCO.2008.18.7229] [PMID]
Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, et al. High frequency of tumorā€infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repairā€proficient colorectal cancer patients. International Journal of Cancer. 2010; 126(11):2635-43. [DOI:10.1002/ijc.24989]
Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood. 2012; 119(19):4430-40. [DOI:10.1182/blood-2011-11-392324] [PMID] [PMCID]
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. The Journal of Experimental Medicine. 2009; 206(13):3015-29. [DOI:10.1084/jem.20090847] [PMID] [PMCID]
Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, et al. LAG-3 expression defines a subset of CD4+ CD25highFoxp3+ regulatory T cells that are expanded at tumor sites. The Journal of Immunology. 2010; 184(11):6545-51. [DOI:10.4049/jimmunol.0903879] [PMID]
Jie H, Gildener-Leapman N, Li J, Srivastava R, Gibson S, Whiteside T, et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. British Journal of Cancer. 2013; 109(10):2629-35. [DOI:10.1038/bjc.2013.645] [PMID] [PMCID]
Colombo MP, Piconese S. Regulatory T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nature Reviews Cancer. 2007; 7(11):880-7. [DOI:10.1038/nrc2250] [PMID]
Chang LY, Lin YC, Mahalingam J, Huang CT, Chen TW, Kang CW, et al. Tumor-derived chemokine CCL5 enhances TGF-β–mediated killing of CD8+ T cells in colon cancer by t-regulatory cell. Cancer research. 2012; 72(5):1092-102. [DOI:10.1158/0008-5472.CAN-11-2493] [PMID]
Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, et al. Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut. 2012; 61(8):1163-71. [DOI:10.1136/gutjnl-2011-300970] [PMID] [PMCID]
Byrne WL, Mills KH, Lederer JA, O’Sullivan GC. Targeting regulatory T cells in cancer. Cancer Research. 2011; 71(22):6915-20. [DOI:10.1158/0008-5472.CAN-11-1156] [PMID] [PMCID]
Medina-Echeverz J, Fioravanti J, Zabala M, Ardaiz N, Prieto J, Berraondo P. Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells. The Journal of Immunology. 2011; 186(2):807-15. [DOI:10.4049/jimmunol.1001483] [PMID]
Bonertz A, Weitz J, Pietsch DHK, Rahbari NN, Schlude C, Ge Y, et al. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. The Journal of Clinical Investigation. 2009; 119(11):3311-21. [DOI:10.1172/JCI39608]
Izhak L, Ambrosino E, Kato S, Parish ST, O’Konek JJ, Weber H, et al. Delicate balance among three types of T cells in concurrent regulation of tumor immunity. Cancer Research. 2013; 73(5):1514-23. [DOI:10.1158/0008-5472.CAN-12-2567] [PMID] [PMCID]
Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nature Medicine. 2011; 17(9):1094-100. [DOI:10.1038/nm.2438] [PMID] [PMCID]
Villanacci V, Not T, Nascimbeni R, Ferrara F, Tommasini A, Manenti S, et al. Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions. Pathology-Journal of the RCPA. 2011; 43(5):465-71. [DOI:10.1097/PAT.0b013e3283485e37]
Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. British Journal of Cancer. 2008; 99(11):1867-73. [DOI:10.1038/sj.bjc.6604756] [PMID] [PMCID]
Lee H, Park D, Kim W, Kim H, Lee H. High FOXP3+ regulatory T-cell density in the sentinel lymph node is associated with downstream non-sentinel lymph-node metastasis in gastric cancer. British Journal of Cancer. 2011; 105(3):413-9. [DOI:10.1038/bjc.2011.248] [PMID] [PMCID]
Khazaie K, Bonertz A, Beckhove P. Current developments with peptide-based human tumor vaccines. Current Opinion in Oncology. 2009; 21(6):524-30. [DOI:10.1097/CCO.0b013e328331a78e] [PMID]
Mougiakakos D. Regulatory T Cells in Colorectal Cancer: From Biology to Prognostic Relevance. Cancers. 2011; 3(2):1708-31. [DOI:10.3390/cancers3021708] [PMID] [PMCID]
Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends in Immunology. 2015; 36(1):3-12. [DOI:10.1016/j.it.2014.08.003] [PMID] [PMCID]
Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Research. 2013; 73(2):539-49. [DOI:10.1158/0008-5472.CAN-12-2325] [PMID]
Singer B, King L. D′ Alessio FR. Regulatory T cells as immunotherapy. 2014; 5:46.