Research article Special Issues

The regulatory function of sphingosine-1-phosphate signaling axis on regulatory T cells in colorectal cancer

  • Received: 06 September 2014 Accepted: 26 January 2015 Published: 08 February 2015
  • In tumors associated with inflammation such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), high numbers of regulatory T cells (Tregs) are associated with both favorable and poor prognoses. The functions of Tregs in CRC remain elusive and have yet to be clearly defined. With new evidence supporting many subsets of Tregs, the research on the development and functions of these cells has begun to come to fruition. The sphingosine 1 phosphate (S1P) pathway was recently reported to regulate the development and function of regulatory T cells. This pathway may shine new light into the pleiotropic nature of these cells in cancer. In this review, we will examine current literature on the many functions of Tregs in CRC and highlight the significance of the S1P signaling pathway in Treg development/function with the implication of novel therapeutic strategies in treatment of CRC patients.

    Citation: Andrew V. Nguyen, Yuan-Yuan Wu, Elaine Y. Lin. The regulatory function of sphingosine-1-phosphate signaling axis on regulatory T cells in colorectal cancer[J]. AIMS Molecular Science, 2015, 1(1): 34-47. doi: 10.3934/molsci.2015.1.34

    Related Papers:

  • In tumors associated with inflammation such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), high numbers of regulatory T cells (Tregs) are associated with both favorable and poor prognoses. The functions of Tregs in CRC remain elusive and have yet to be clearly defined. With new evidence supporting many subsets of Tregs, the research on the development and functions of these cells has begun to come to fruition. The sphingosine 1 phosphate (S1P) pathway was recently reported to regulate the development and function of regulatory T cells. This pathway may shine new light into the pleiotropic nature of these cells in cancer. In this review, we will examine current literature on the many functions of Tregs in CRC and highlight the significance of the S1P signaling pathway in Treg development/function with the implication of novel therapeutic strategies in treatment of CRC patients.


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    [1] Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30: 626-635. doi: 10.1016/j.immuni.2009.05.002
    [2] Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6: 345-352.
    [3] Maggi E, Cosmi L, Liotta F, et al. (2005) Thymic regulatory T cells. Autoimmun Rev 4: 579-586. doi: 10.1016/j.autrev.2005.04.010
    [4] Mougiakakos D, Choudhury A, Lladser A, et al. (2010) Regulatory T cells in cancer. Adv Cancer Res 107: 57-117. doi: 10.1016/S0065-230X(10)07003-X
    [5] Jonuleit H, Schmitt E (2003) The regulatory T cell family: distinct subsets and their interrelations. J Immunol 171: 6323-6327. doi: 10.4049/jimmunol.171.12.6323
    [6] Mucida D, Kutchukhidze N, Erazo A, et al. (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clini Invest 115: 1923-1933. doi: 10.1172/JCI24487
    [7] Sakaguchi S, Sakaguchi N, Asano M, et al. (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151-1164.
    [8] Roncarolo MG, Gregori S, Battaglia M, et al. (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212: 28-50. doi: 10.1111/j.0105-2896.2006.00420.x
    [9] Setoguchi R, Hori S, Takahashi T, et al. (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201: 723-735. doi: 10.1084/jem.20041982
    [10] Barron L, Dooms H, Hoyer KK, et al. (2010) Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 185: 6426-6430. doi: 10.4049/jimmunol.0903940
    [11] Read S, Mauze S, Asseman C, et al. (1998) CD38+ CD45RB(low) CD4+ T cells: a population of T cells with immune regulatory activities in vitro. Eur J Immunol 28: 3435-3447. doi: 10.1002/(SICI)1521-4141(199811)28:11<3435::AID-IMMU3435>3.0.CO;2-P
    [12] Fu S, Yopp AC, Mao X, et al. (2004) CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential. Am J Transplant 4: 65-78. doi: 10.1046/j.1600-6143.2003.00293.x
    [13] Allakhverdi Z, Fitzpatrick D, Boisvert A, et al. (2006) Expression of CD103 identifies human regulatory T-cell subsets. J Allergy Clin Immunol 118: 1342-1349. doi: 10.1016/j.jaci.2006.07.034
    [14] Brunkow ME, Jeffery EW, Hjerrild KA, et al. (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27: 68-73.
    [15] Chatila TA, Blaeser F, Ho N, et al. (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clini Invest 106: R75-81. doi: 10.1172/JCI11679
    [16] Bennett CL, Christie J, Ramsdell F, et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27: 20-21. doi: 10.1038/83713
    [17] Allan SE, Passerini L, Bacchetta R, et al. (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clini Invest 115: 3276-3284. doi: 10.1172/JCI24685
    [18] Tang Q, Bluestone JA (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9: 239-244. doi: 10.1038/ni1572
    [19] LeGuern C (2003) Regulation of T-cell functions by MHC class II self-presentation. Trends Immunol 24: 633-638. doi: 10.1016/j.it.2003.10.010
    [20] Coutinho A, Caramalho I, Seixas E, et al. (2005) Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. Curr Top Microbiol 293: 43-71.
    [21] Burchill MA, Yang J, Vang KB, et al. (2008) Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28: 112-121. doi: 10.1016/j.immuni.2007.11.022
    [22] Liston A, Nutsch KM, Farr AG, et al. (2008) Differentiation of regulatory Foxp3+ T cells in the thymic cortex. P Natl Acad Sci USA 105: 11903-11908. doi: 10.1073/pnas.0801506105
    [23] Gershon RK, Kondo K (1970) Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18: 723-737.
    [24] Lopes JE, Torgerson TR, Schubert LA, et al. (2006) Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 177: 3133-3142. doi: 10.4049/jimmunol.177.5.3133
    [25] Wu Y, Borde M, Heissmeyer V, et al. (2006) FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126: 375-387. doi: 10.1016/j.cell.2006.05.042
    [26] Shimizu J, Yamazaki S, Takahashi T, et al. (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3: 135-142. doi: 10.1038/ni759
    [27] Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22: 531-562. doi: 10.1146/annurev.immunol.21.120601.141122
    [28] Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182: 459-465. doi: 10.1084/jem.182.2.459
    [29] Walunas TL, Lenschow DJ, Bakker CY, et al. (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1: 405-413. doi: 10.1016/1074-7613(94)90071-X
    [30] Onishi Y, Fehervari Z, Yamaguchi T, et al. (2008) Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. P Natl Acad Sci USA 105: 10113-10118. doi: 10.1073/pnas.0711106105
    [31] Belladonna ML, Puccetti P, Orabona C, et al. (2007) Immunosuppression via tryptophan catabolism: the role of kynurenine pathway enzymes. Transplantation 84: S17-20.
    [32] Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol 29: 429-435. doi: 10.1016/j.it.2008.06.005
    [33] Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199: 1401-1408. doi: 10.1084/jem.20040249
    [34] Kretschmer K, Apostolou I, Hawiger D, et al. (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6: 1219-1227. doi: 10.1038/ni1265
    [35] Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204: 1757-1764. doi: 10.1084/jem.20070590
    [36] Selvaraj RK, Geiger TL (2007) A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J Iimmunol 178: 7667-7677. doi: 10.4049/jimmunol.178.12.7667
    [37] Faria AM, Weiner HL (2006) Oral tolerance and TGF-beta-producing cells. Inflamm Allergy Drug Targets 5: 179-190. doi: 10.2174/187152806778256034
    [38] Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182: 207-214. doi: 10.1034/j.1600-065X.2001.1820117.x
    [39] Carrier Y, Yuan J, Kuchroo VK, et al. (2007) Th3 cells in peripheral tolerance. II. TGF-beta-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity. J Immunol 178: 172-178.
    [40] Walker MR, Carson BD, Nepom GT, et al. (2005) De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. P Natl Acad Sci USA 102: 4103-4108. doi: 10.1073/pnas.0407691102
    [41] Wilczynski JR, Radwan M, Kalinka J (2008) The characterization and role of regulatory T cells in immune reactions. Front Biosci 13: 2266-2274. doi: 10.2741/2840
    [42] Mazza G, Sabatos-Peyton CA, Protheroe RE, et al. (2010) Isolation and characterization of human interleukin-10-secreting T cells from peripheral blood. Hum Immunol 71: 225-234. doi: 10.1016/j.humimm.2009.12.003
    [43] Pinchuk IV, Beswick EJ, Saada JI, et al. (2011) Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells. Gastroenterology 140: 2019-2030. doi: 10.1053/j.gastro.2011.02.059
    [44] Wingo PA, Ries LA, Parker SL, et al. (1998) Long-term cancer patient survival in the United States. Cancer Epidemiol Biomarkers Prev 7: 271-282.
    [45] Cannon-Albright LA, Skolnick MH, Bishop DT, et al. (1988) Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 319: 533-537. doi: 10.1056/NEJM198809013190902
    [46] Peltomaki P, de la Chapelle A (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res 71: 93-119. doi: 10.1016/S0065-230X(08)60097-4
    [47] Hawkins NJ, Ward RL (2001) Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer I 93: 1307-1313. doi: 10.1093/jnci/93.17.1307
    [48] Fishel R, Lescoe MK, Rao MR, et al. (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027-1038. doi: 10.1016/0092-8674(93)90546-3
    [49] Al-Tassan N, Chmiel NH, Maynard J, et al. (2002) Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet 30: 227-232. doi: 10.1038/ng828
    [50] Grady WM, Carethers JM (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135: 1079-1099. doi: 10.1053/j.gastro.2008.07.076
    [51] Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87: 159-170. doi: 10.1016/S0092-8674(00)81333-1
    [52] MacPhee M, Chepenik KP, Liddell RA, et al. (1995) The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81: 957-966. doi: 10.1016/0092-8674(95)90015-2
    [53] Shoemaker AR, Gould KA, Luongo C, et al. (1997) Studies of neoplasia in the Min mouse. Biochimica et biophysica acta 1332: F25-48.
    [54] de Miranda NF, Hes FJ, van Wezel T, et al. (2012) Role of the microenvironment in the tumourigenesis of microsatellite unstable and MUTYH-associated polyposis colorectal cancers. Mutagenesis 27: 247-253. doi: 10.1093/mutage/ger077
    [55] Salama P, Phillips M, Grieu F, et al. (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27: 186-192. doi: 10.1200/JCO.2008.18.7229
    [56] Ladoire S, Martin F, Ghiringhelli F (2011) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60: 909-918. doi: 10.1007/s00262-011-1046-y
    [57] Boland CR (2010) Chronic inflammation, colorectal cancer and gene polymorphisms. Digestive diseases 28: 590-595. doi: 10.1159/000320053
    [58] Danese S, Mantovani A Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene 29: 3313-3323.
    [59] Chaput N, Louafi S, Bardier A, et al. (2009) Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58: 520-529. doi: 10.1136/gut.2008.158824
    [60] Brudvik KW, Henjum K, Aandahl EM, et al. (2012) Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer. Cancer Immunol Immunother 61: 1045-1053. doi: 10.1007/s00262-011-1174-4
    [61] Zeng JC, Zhang Z, Li TY, et al. (2013) Assessing the role of IL-35 in colorectal cancer progression and prognosis. Int J Clin Exp Pathol 6: 1806-1816.
    [62] Bates GJ, Fox SB, Han C, et al. (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24: 5373-5380. doi: 10.1200/JCO.2006.05.9584
    [63] Fu J, Xu D, Liu Z, et al. (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132: 2328-2339. doi: 10.1053/j.gastro.2007.03.102
    [64] Betts G, Jones E, Junaid S, et al. (2012) Suppression of tumour-specific CD4(+) T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 61: 1163-1171. doi: 10.1136/gutjnl-2011-300970
    [65] Bacic D, Uravic M, Bacic R, et al. (2011) Augmentation of regulatory T cells (CD4+CD25+Foxp3+) correlates with tumor stage in patients with colorectal cancer. Coll Antropol 35 Suppl 2: 65-68.
    [66] Mempel TR, Pittet MJ, Khazaie K, et al. (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25: 129-141. doi: 10.1016/j.immuni.2006.04.015
    [67] Slaney CY, Rautela J, Parker BS (2013) The emerging role of immunosurveillance in dictating metastatic spread in breast cancer. Cancer Res 73: 5852-5857. doi: 10.1158/0008-5472.CAN-13-1642
    [68] Koebel CM, Vermi W, Swann JB, et al. (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450: 903-907. doi: 10.1038/nature06309
    [69] Bonertz A, Weitz J, Pietsch DH, et al. (2009) Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clini Invest 119: 3311-3321.
    [70] Duchmann R, May E, Heike M, et al. (1999) T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut 44: 812-818. doi: 10.1136/gut.44.6.812
    [71] Naito Y, Saito K, Shiiba K, et al. (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58: 3491-3494.
    [72] Golby SJ, Chinyama C, Spencer J (2002) Proliferation of T-cell subsets that contact tumour cells in colorectal cancer. Clin Exp Immunol 127: 85-91. doi: 10.1046/j.1365-2249.2002.01730.x
    [73] Le Gouvello S, Bastuji-Garin S, Aloulou N, et al. (2008) High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut 57: 772-779. doi: 10.1136/gut.2007.123794
    [74] Nosho K, Baba Y, Tanaka N, et al. (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222: 350-366. doi: 10.1002/path.2774
    [75] Gooden MJ, de Bock GH, Leffers N, et al. (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Brit J Cancer 105: 93-103. doi: 10.1038/bjc.2011.189
    [76] Sinicrope FA, Rego RL, Ansell SM, et al. (2009) Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 137: 1270-1279. doi: 10.1053/j.gastro.2009.06.053
    [77] Katz SC, Bamboat ZM, Maker AV, et al. (2013) Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 20: 946-955. doi: 10.1245/s10434-012-2668-9
    [78] Blatner NR, Mulcahy MF, Dennis KL, et al. (2012) Expression of RORgammat marks a pathogenic regulatory T cell subset in human colon cancer. Sci Transl Med 4: 164ra159.
    [79] Awasthi A, Kuchroo VK (2009) Th17 cells: from precursors to players in inflammation and infection. Int Immunol 21: 489-498. doi: 10.1093/intimm/dxp021
    [80] Liu Z, Huang Q, Liu G, et al. (2014) Presence of FOXP3(+)Treg cells is correlated with colorectal cancer progression. Int J Clin Exp Med 7: 1781-1785.
    [81] Sojka DK, Huang YH, Fowell DJ (2008) Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 124: 13-22. doi: 10.1111/j.1365-2567.2008.02813.x
    [82] Ishimaru N, Nitta T, Arakaki R, et al. (2010) In situ patrolling of regulatory T cells is essential for protecting autoimmune exocrinopathy. PloS One 5: e8588. doi: 10.1371/journal.pone.0008588
    [83] Akeus P, Langenes V, von Mentzer A, et al. (2014) Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice. Cancer Immunol Immunother 63: 807-819. doi: 10.1007/s00262-014-1555-6
    [84] Michaud J, Im DS, Hla T (2010) Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation. J Immunol 184: 1475-1483. doi: 10.4049/jimmunol.0901586
    [85] Ishimaru N, Yamada A, Nitta T, et al. (2012) CCR7 with S1P1 signaling through AP-1 for migration of Foxp3+ regulatory T-cells controls autoimmune exocrinopathy. Am J Pathol 180: 199-208. doi: 10.1016/j.ajpath.2011.09.027
    [86] Goetzl EJ, Liao JJ, Huang MC (2008) Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity. Biochimica et biophysica acta 1781: 503-507. doi: 10.1016/j.bbalip.2008.03.001
    [87] Wang W, Graeler MH, Goetzl EJ (2004) Physiological sphingosine 1-phosphate requirement for optimal activity of mouse CD4+ regulatory T Cells. FASEB J 18: 1043-1045.
    [88] Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5: 560-570. doi: 10.1038/nri1650
    [89] Pyne S, Pyne NJ (2011) Translational aspects of sphingosine 1-phosphate biology. Trends Mol Med 17: 463-472. doi: 10.1016/j.molmed.2011.03.002
    [90] Kohama T, Olivera A, Edsall L, et al. (1998) Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 273: 23722-23728. doi: 10.1074/jbc.273.37.23722
    [91] Liu H, Chakravarty D, Maceyka M, et al. (2002) Sphingosine kinases: a novel family of lipid kinases. Prog Nucleic Acid Res Mol Biol 71: 493-511. doi: 10.1016/S0079-6603(02)71049-0
    [92] Wang W, Huang MC, Goetzl EJ (2007) Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J Immunol 178: 4885-4890. doi: 10.4049/jimmunol.178.8.4885
    [93] Sawicka E, Dubois G, Jarai G, et al. (2005) The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol 175: 7973-7980. doi: 10.4049/jimmunol.175.12.7973
    [94] Liu G, Yang K, Burns S, et al. (2010) The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 11: 1047-1056. doi: 10.1038/ni.1939
    [95] Snider AJ, Orr Gandy KA, Obeid LM (2010) Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 92: 707-715. doi: 10.1016/j.biochi.2010.02.008
    [96] Spiegel S, Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11: 403-415. doi: 10.1038/nri2974
    [97] Maceyka M, Harikumar KB, Milstien S, et al. (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22: 50-60. doi: 10.1016/j.tcb.2011.09.003
    [98] Schwalm S, Pfeilschifter J, Huwiler A (2013) Sphingosine-1-phosphate: a Janus-faced mediator of fibrotic diseases. Biochim Biophys Acta 1831: 239-250. doi: 10.1016/j.bbalip.2012.07.022
    [99] Nguyen AV, Wu YY, Liu Q, et al. (2013) STAT3 in Epithelial Cells Regulates Inflammation and Tumor Progression to Malignant State in Colon. Neoplasia 15: 998-1008. doi: 10.1593/neo.13952
    [100] Liang J, Nagahashi M, Kim EY, et al. (2013) Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23: 107-120. doi: 10.1016/j.ccr.2012.11.013
    [101] Lee H, Herrmann A, Deng JH, et al. (2009) Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15: 283-293. doi: 10.1016/j.ccr.2009.02.015
    [102] Nagahashi M, Hait NC, Maceyka M, et al. (2014) Sphingosine-1-phosphate in chronic intestinal inflammation and cancer. Adv Biol Regul 54: 112-120. doi: 10.1016/j.jbior.2013.10.001
    [103] Daniel C, Sartory N, Zahn N, et al. (2007) FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 178: 2458-2468. doi: 10.4049/jimmunol.178.4.2458
    [104] Bos PD, Rudensky AY (2012) Treg cells in cancer: a case of multiple personality disorder. Sci Transl Med 4: 164fs144.
    [105] Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367: 1596-1606.
    [106] Nguyen AV, Wu YY, Lin EY (2014) STAT3 and sphingosine-1-phosphate in inflammation-associated colorectal cancer. World J Gastroenterol 20: 10279-10287. doi: 10.3748/wjg.v20.i30.10279
    [107] Khan S, Burt DJ, Ralph C, et al. (2011) Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells. Clin Immunol 138: 85-96. doi: 10.1016/j.clim.2010.09.011
    [108] Saha A, Chatterjee SK (2010) Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer. Scand J Immunol 71: 70-82. doi: 10.1111/j.1365-3083.2009.02355.x
    [109] Yano H, Thakur A, Tomaszewski EN, et al. (2014) Ipilimumab augments antitumor activity of bispecific antibody-armed T cells. J Transl Med 12: 191. doi: 10.1186/1479-5876-12-191
    [110] Liu H, Hu B, Xu D, et al. (2003) CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4. J Immunol 171: 5012-5017. doi: 10.4049/jimmunol.171.10.5012
    [111] von Boehmer H, Daniel C (2013) Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov 12: 51-63.
    [112] Rech AJ, Mick R, Martin S, et al. (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4: 134ra162.
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