Regulatory T cells (Tregs) were initially described as "suppressive" lymphocytes in the 1980s. However, it took almost 20 years until the concept of Treg-mediated immune control in its present form was finally established. Tregs are obligatory for self-tolerance and defects within their population lead to severe autoimmune disorders. On the other hand Tregs may promote tolerance for tumor antigens and even hamper efforts to overcome it. Intratumoral and systemic accumulation of Tregs has been observed in various types of cancer and is often linked to worse disease course and outcome. Increase of circulating Tregs, as well as their presence in mesenteric lymph nodes and tumor tissue of patients with colorectal cancer de facto suggests a strong involvement of Tregs in the antitumor control. This review will focus on the Treg biology in view of colorectal cancer, means of Treg accumulation and the controversies regarding their prognostic significance. In addition, a concise overview will be given on how Tregs and their function can be targeted in cancer patients in order to bolster an inherent immune response and/or increase the efficacy of immunotherapeutic approaches.
References
[1]
Dunn, G.P.; Old, L.J.; Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21, 137–148.
[2]
Kawakami, Y.; Rosenberg, S.A. Human tumor antigens recognized by t-cells. Immunol. Res. 1997, 16, 313–339.
[3]
Kappler, J.W.; Roehm, N.; Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 1987, 49, 273–280.
Gershon, R.K.; Kondo, K. Cell interactions in the induction of tolerance: The role of thymic lymphocytes. Immunology 1970, 18, 723–737.
[7]
Sakaguchi, S.; Sakaguchi, N.; Asano, M.; Itoh, M.; Toda, M. 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. 1995, 155, 1151–1164.
[8]
Baecher-Allan, C.; Brown, J.A.; Freeman, G.J.; Hafler, D.A. Cd4+cd25high regulatory cells in human peripheral blood. J. Immunol. 2001, 167, 1245–1253.
[9]
Dieckmann, D.; Plottner, H.; Berchtold, S.; Berger, T.; Schuler, G. Ex vivo isolation and characterization of cd4(+)cd25(+) t cells with regulatory properties from human blood. J. Exp. Med. 2001, 193, 1303–1310.
[10]
Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of cd4+cd25+ regulatory t cells. Nat. Immunol. 2003, 4, 330–336.
[11]
Roncador, G.; Brown, P.J.; Maestre, L.; Hue, S.; Martinez-Torrecuadrada, J.L.; Ling, K.L.; Pratap, S.; Toms, C.; Fox, B.C.; Cerundolo, V.; Powrie, F.; Banham, A.H. Analysis of foxp3 protein expression in human cd4+cd25+ regulatory t cells at the single-cell level. Eur. J. Immunol. 2005, 35, 1681–1691.
[12]
Walker, M.R.; Kasprowicz, D.J.; Gersuk, V.H.; Benard, A.; Van Landeghen, M.; Buckner, J.H.; Ziegler, S.F. Induction of foxp3 and acquisition of t regulatory activity by stimulated human cd4+cd25- t cells. J. Clin. Invest. 2003, 112, 1437–1443.
[13]
Bennett, C.L.; Christie, J.; Ramsdell, F.; Brunkow, M.E.; Ferguson, P.J.; Whitesell, L.; Kelly, T.E.; Saulsbury, F.T.; Chance, P.F.; Ochs, H.D. The immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (ipex) is caused by mutations of foxp3. Nat. Genet. 2001, 27, 20–21.
[14]
Brunkow, M.E.; Jeffery, E.W.; Hjerrild, K.A.; Paeper, B.; Clark, L.B.; Yasayko, S.A.; Wilkinson, J.E.; Galas, D.; Ziegler, S.F.; Ramsdell, F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 2001, 27, 68–73.
[15]
Wing, K.; Sakaguchi, S. Regulatory t cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 2010, 11, 7–13.
[16]
Valencia, X.; Yarboro, C.; Illei, G.; Lipsky, P.E. Deficient cd4+cd25high t regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 2007, 178, 2579–2588.
[17]
Venken, K.; Hellings, N.; Broekmans, T.; Hensen, K.; Rummens, J.L.; Stinissen, P. Natural naive cd4+cd25+cd127low regulatory t cell (treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory treg homeostasis during disease progression. J. Immunol. 2008, 180, 6411–6420.
[18]
Berendt, M.J.; North, R.J. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J. Exp. Med. 1980, 151, 69–80.
[19]
Fujimoto, S.; Greene, M.I.; Sehon, A.H. Regualtion of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts. J. Immunol. 1976, 116, 791–799.
[20]
Fujimoto, S.; Greene, M.I.; Sehon, A.H. Regulation of the immune response to tumor antigens. Ii. The nature of immunosuppressor cells in tumor-bearing hosts. J. Immunol. 1976, 116, 800–806.
[21]
Sakaguchi, S.; Miyara, M.; Costantino, C.M.; Hafler, D.A. Foxp3+ regulatory t cells in the human immune system. Nat. Rev. Immunol. 2010, 10, 490–500.
[22]
Woo, E.Y.; Chu, C.S.; Goletz, T.J.; Schlienger, K.; Yeh, H.; Coukos, G.; Rubin, S.C.; Kaiser, L.R.; June, C.H. Regulatory cd4(+)cd25(+) t cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001, 61, 4766–4772.
[23]
Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.; Conejo-Garcia, J.R.; Zhang, L.; Burow, M.; Zhu, Y.; Wei, S.; Kryczek, I.; Daniel, B.; Gordon, A.; Myers, L.; Lackner, A.; Disis, M.L.; Knutson, K.L.; Chen, L.; Zou, W. Specific recruitment of regulatory t cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004, 10, 942–949.
[24]
Jemal, A.; Tiwari, R.C.; Murray, T.; Ghafoor, A.; Samuels, A.; Ward, E.; Feuer, E.J.; Thun, M.J. Cancer statistics, 2004. CA Cancer J. Clin. 2004, 54, 8–29.
[25]
Shevach, E.M. From vanilla to 28 flavors: Multiple varieties of t regulatory cells. Immunity 2006, 25, 195–201.
[26]
Feuerer, M.; Hill, J.A.; Mathis, D.; Benoist, C. Foxp3+ regulatory t cells: Differentiation, specification, subphenotypes. Nat. Immunol. 2009, 10, 689–695.
[27]
Seddiki, N.; Santner-Nanan, B.; Tangye, S.G.; Alexander, S.I.; Solomon, M.; Lee, S.; Nanan, R.; Fazekas de Saint Groth, B. Persistence of naive cd45ra+ regulatory t cells in adult life. Blood 2006, 107, 2830–2838.
[28]
Seddiki, N.; Santner-Nanan, B.; Martinson, J.; Zaunders, J.; Sasson, S.; Landay, A.; Solomon, M.; Selby, W.; Alexander, S.I.; Nanan, R.; Kelleher, A.; Fazekas de St Groth, B. Expression of interleukin (il)-2 and il-7 receptors discriminates between human regulatory and activated t cells. J. Exp. Med. 2006, 203, 1693–1700.
[29]
Liu, W.; Putnam, A.L.; Xu-Yu, Z.; Szot, G.L.; Lee, M.R.; Zhu, S.; Gottlieb, P.A.; Kapranov, P.; Gingeras, T.R.; Fazekas de St Groth, B.; Clayberger, C.; Soper, D.M.; Ziegler, S.F.; Bluestone, J.A. Cd127 expression inversely correlates with foxp3 and suppressive function of human cd4+ t reg cells. J. Exp. Med. 2006, 203, 1701–1711.
[30]
Groux, H.; O'Garra, A.; Bigler, M.; Rouleau, M.; Antonenko, S.; de Vries, J.E.; Roncarolo, M.G. A cd4+ t-cell subset inhibits antigen-specific t-cell responses and prevents colitis. Nature 1997, 389, 737–742.
[31]
Vieira, P.L.; Christensen, J.R.; Minaee, S.; O'Neill, E.J.; Barrat, F.J.; Boonstra, A.; Barthlott, T.; Stockinger, B.; Wraith, D.C.; O'Garra, A. Il-10-secreting regulatory t cells do not express foxp3 but have comparable regulatory function to naturally occurring cd4+cd25+ regulatory t cells. J. Immunol. 2004, 172, 5986–5993.
Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral cd4+cd25- naive t cells to cd4+cd25+ regulatory t cells by tgf-beta induction of transcription factor foxp3. J. Exp. Med. 2003, 198, 1875–1886.
[34]
Apostolou, I.; von Boehmer, H. In vivo instruction of suppressor commitment in naive t cells. J. Exp. Med. 2004, 199, 1401–1408.
[35]
Wong, J.; Obst, R.; Correia-Neves, M.; Losyev, G.; Mathis, D.; Benoist, C. Adaptation of tcr repertoires to self-peptides in regulatory and nonregulatory cd4+ t cells. J. Immunol. 2007, 178, 7032–7041.
[36]
Wei, S.; Kryczek, I.; Zou, L.; Daniel, B.; Cheng, P.; Mottram, P.; Curiel, T.; Lange, A.; Zou, W. Plasmacytoid dendritic cells induce cd8+ regulatory t cells in human ovarian carcinoma. Cancer Res. 2005, 65, 5020–5026.
[37]
Hoechst, B.; Ormandy, L.A.; Ballmaier, M.; Lehner, F.; Kruger, C.; Manns, M.P.; Greten, T.F.; Korangy, F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces cd4(+)cd25(+)foxp3(+) t cells. Gastroenterolog. 2008, 135, 234–243.
[38]
Hahn, B.H.; Singh, R.P.; La Cava, A.; Ebling, F.M. Tolerogenic treatment of lupus mice with consensus peptide induces foxp3-expressing, apoptosis-resistant, tgfbeta-secreting cd8+ t cell suppressors. J. Immunol. 2005, 175, 7728–7737.
[39]
Filaci, G.; Fenoglio, D.; Fravega, M.; Ansaldo, G.; Borgonovo, G.; Traverso, P.; Villaggio, B.; Ferrera, A.; Kunkl, A.; Rizzi, M.; Ferrera, F.; Balestra, P.; Ghio, M.; Contini, P.; Setti, M.; Olive, D.; Azzarone, B.; Carmignani, G.; Ravetti, J.L.; Torre, G.; Indiveri, F. Cd8+ cd28- t regulatory lymphocytes inhibiting t cell proliferative and cytotoxic functions infiltrate human cancers. J. Immunol. 2007, 179, 4323–4334.
Fischer, K.; Voelkl, S.; Heymann, J.; Przybylski, G.K.; Mondal, K.; Laumer, M.; Kunz-Schughart, L.; Schmidt, C.A.; Andreesen, R.; Mackensen, A. Isolation and characterization of human antigen-specific tcr alpha beta+ cd4(-)cd8- double-negative regulatory t cells. Blood 2005, 105, 2828–2835.
[42]
Peng, G.; Wang, H.Y.; Peng, W.; Kiniwa, Y.; Seo, K.H.; Wang, R.F. Tumor-infiltrating gammadelta t cells suppress t and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 2007, 27, 334–348.
[43]
Tran, D.Q.; Glass, D.D.; Uzel, G.; Darnell, D.A.; Spalding, C.; Holland, S.M.; Shevach, E.M. Analysis of adhesion molecules, target cells, and role of il-2 in human foxp3+ regulatory t cell suppressor function. J. Immunol. 2009, 182, 2929–2938.
[44]
Strauss, L.; Bergmann, C.; Szczepanski, M.; Gooding, W.; Johnson, J.T.; Whiteside, T.L. A unique subset of cd4+cd25highfoxp3+ t cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin. Cancer Res. 2007, 13, 4345–4354.
Yaqub, S.; Henjum, K.; Mahic, M.; Jahnsen, F.L.; Aandahl, E.M.; Bjornbeth, B.A.; Tasken, K. Regulatory t cells in colorectal cancer patients suppress anti-tumor immune activity in a cox-2 dependent manner. Cancer Immunol. Immunother. 2008, 57, 813–821.
[49]
Mandapathil, M.; Szczepanski, M.J.; Szajnik, M.; Ren, J.; Jackson, E.K.; Johnson, J.T.; Gorelik, E.; Lang, S.; Whiteside, T.L. Adenosine and prostaglandin e2 cooperate in the suppression of immune responses mediated by adaptive regulatory t cells. J. Biol. Chem. 2010, 285, 27571–27580.
Bardel, E.; Larousserie, F.; Charlot-Rabiega, P.; Coulomb-L'Hermine, A.; Devergne, O. Human cd4+ cd25+ foxp3+ regulatory t cells do not constitutively express il-35. J. Immunol. 2008, 181, 6898–6905.
[53]
Cao, X.; Cai, S.F.; Fehniger, T.A.; Song, J.; Collins, L.I.; Piwnica-Worms, D.R.; Ley, T.J. Granzyme b and perforin are important for regulatory t cell-mediated suppression of tumor clearance. Immunity 2007, 27, 635–646.
[54]
Ren, X.; Ye, F.; Jiang, Z.; Chu, Y.; Xiong, S.; Wang, Y. Involvement of cellular death in trail/dr5-dependent suppression induced by cd4(+)cd25(+) regulatory t cells. Cell Death Differ. 2007, 14, 2076–2084.
Tadokoro, C.E.; Shakhar, G.; Shen, S.; Ding, Y.; Lino, A.C.; Maraver, A.; Lafaille, J.J.; Dustin, M.L. Regulatory t cells inhibit stable contacts between cd4+ t cells and dendritic cells in vivo. J. Exp. Med. 2006, 203, 505–511.
[57]
Read, S.; Malmstrom, V.; Powrie, F. Cytotoxic t lymphocyte-associated antigen 4 plays an essential role in the function of cd25(+)cd4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 2000, 192, 295–302.
[58]
Mellor, A.L.; Munn, D.H. Ido expression by dendritic cells: Tolerance and tryptophan catabolism. Nat. Rev. Immunol. 2004, 4, 762–774.
[59]
Huang, C.T.; Workman, C.J.; Flies, D.; Pan, X.; Marson, A.L.; Zhou, G.; Hipkiss, E.L.; Ravi, S.; Kowalski, J.; Levitsky, H.I.; Powell, J.D.; Pardoll, D.M.; Drake, C.G.; Vignali, D.A. Role of lag-3 in regulatory t cells. Immunity 2004, 21, 503–513.
[60]
Sarris, M.; Andersen, K.G.; Randow, F.; Mayr, L.; Betz, A.G. Neuropilin-1 expression on regulatory t cells enhances their interactions with dendritic cells during antigen recognition. Immunity 2008, 28, 402–413.
[61]
Wilhelm, K.; Ganesan, J.; Muller, T.; Durr, C.; Grimm, M.; Beilhack, A.; Krempl, C.D.; Sorichter, S.; Gerlach, U.V.; Juttner, E.; Zerweck, A.; Gartner, F.; Pellegatti, P.; Di Virgilio, F.; Ferrari, D.; Kambham, N.; Fisch, P.; Finke, J.; Idzko, M.; Zeiser, R. Graft-versus-host disease is enhanced by extracellular atp activating p2×(7)r. Nat. Med. 2010, 16, 1434–1438.
[62]
Deaglio, S.; Dwyer, K.M.; Gao, W.; Friedman, D.; Usheva, A.; Erat, A.; Chen, J.F.; Enjyoji, K.; Linden, J.; Oukka, M.; Kuchroo, V.K.; Strom, T.B.; Robson, S.C. Adenosine generation catalyzed by cd39 and cd73 expressed on regulatory t cells mediates immune suppression. J. Exp. Med. 2007, 204, 1257–1265.
[63]
Wilson, J.M.; Ross, W.G.; Agbai, O.N.; Frazier, R.; Figler, R.A.; Rieger, J.; Linden, J.; Ernst, P.B. The a2b adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol. 2009, 182, 4616–4623.
[64]
Bopp, T.; Becker, C.; Klein, M.; Klein-Hessling, S.; Palmetshofer, A.; Serfling, E.; Heib, V.; Becker, M.; Kubach, J.; Schmitt, S.; Stoll, S.; Schild, H.; Staege, M.S.; Stassen, M.; Jonuleit, H.; Schmitt, E. Cyclic adenosine monophosphate is a key component of regulatory t cell-mediated suppression. J. Exp. Med. 2007, 204, 1303–1310.
[65]
Pandiyan, P.; Zheng, L.; Ishihara, S.; Reed, J.; Lenardo, M.J. Cd4+cd25+foxp3+ regulatory t cells induce cytokine deprivation-mediated apoptosis of effector cd4+ t cells. Nat. Immunol. 2007, 8, 1353–1362.
[66]
Tran, D.Q.; Andersson, J.; Hardwick, D.; Bebris, L.; Illei, G.G.; Shevach, E.M. Selective expression of latency-associated peptide (lap) and il-1 receptor type i/ii (cd121a/cd121b) on activated human foxp3+ regulatory t cells allows for their purification from expansion cultures. Blood 2009, 113, 5125–5133.
[67]
Yan, Z.; Garg, S.K.; Kipnis, J.; Banerjee, R. Extracellular redox modulation by regulatory t cells. Nat. Chem. Biol. 2009, 5, 721–723.
[68]
Yan, Z.; Garg, S.K.; Banerjee, R. Regulatory t cells interfere with glutathione metabolism in dendritic cells and t cells. J. Biol. Chem. 2010.
[69]
Mougiakakos, D.; Johansson, C.C.; Kiessling, R. Naturally occurring regulatory t cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 2009, 113, 3542–3545.
[70]
Mougiakakos, D.; Johansson, C.C.; Jitschin, R.; Bottcher, M.; Kiessling, R. Increased thioredoxin-1 production in human naturally occurring regulatory t cells confers enhanced tolerance to oxidative stress. Blood 2010, 117, 857–861.
[71]
Jordan, J.T.; Sun, W.; Hussain, S.F.; DeAngulo, G.; Prabhu, S.S.; Heimberger, A.B. Preferential migration of regulatory t cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol. Immunother. 2008, 57, 123–131.
[72]
Tan, M.C.; Goedegebuure, P.S.; Belt, B.A.; Flaherty, B.; Sankpal, N.; Gillanders, W.E.; Eberlein, T.J.; Hsieh, C.S.; Linehan, D.C. Disruption of ccr5-dependent homing of regulatory t cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 2009, 182, 1746–1755.
[73]
Mizukami, Y.; Kono, K.; Kawaguchi, Y.; Akaike, H.; Kamimura, K.; Sugai, H.; Fujii, H. Ccl17 and ccl22 chemokines within tumor microenvironment are related to accumulation of foxp3+ regulatory t cells in gastric cancer. Int. J. Cancer 2008, 122, 2286–2293.
[74]
Gobert, M.; Treilleux, I.; Bendriss-Vermare, N.; Bachelot, T.; Goddard-Leon, S.; Arfi, V.; Biota, C.; Doffin, A.C.; Durand, I.; Olive, D.; Perez, S.; Pasqual, N.; Faure, C.; Ray-Coquard, I.; Puisieux, A.; Caux, C.; Blay, J.Y.; Menetrier-Caux, C. 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. 2009, 69, 2000–2009.
[75]
Wolf, D.; Rumpold, H.; Koppelstatter, C.; Gastl, G.A.; Steurer, M.; Mayer, G.; Gunsilius, E.; Tilg, H.; Wolf, A.M. Telomere length of in vivo expanded cd4(+)cd25 (+) regulatory t-cells is preserved in cancer patients. Cancer Immunol. Immunother. 2006, 55, 1198–1208.
Lal, G.; Bromberg, J.S. Epigenetic mechanisms of regulation of foxp3 expression. Blood 2009, 114, 3727–3735.
[78]
Yamagiwa, S.; Gray, J.D.; Hashimoto, S.; Horwitz, D.A. A role for TGF-beta in the generation and expansion of cd4+cd25+ regulatory t cells from human peripheral blood. J. Immunol. 2001, 166, 7282–7289.
[79]
Bergmann, C.; Strauss, L.; Wang, Y.; Szczepanski, M.J.; Lang, S.; Johnson, J.T.; Whiteside, T.L. T regulatory type 1 cells in squamous cell carcinoma of the head and neck: Mechanisms of suppression and expansion in advanced disease. Clin. Cancer Res. 2008, 14, 3706–3715.
[80]
Gray, C.P.; Arosio, P.; Hersey, P. Association of increased levels of heavy-chain ferritin with increased cd4+ cd25+ regulatory t-cell levels in patients with melanoma. Clin. Cancer Res. 2003, 9, 2551–2559.
[81]
Bergmann, C.; Strauss, L.; Zeidler, R.; Lang, S.; Whiteside, T.L. Expansion of human t regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res. 2007, 67, 8865–8873.
[82]
El Andaloussi, A.; Lesniak, M.S. Cd4+ cd25+ foxp3+ t-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J. Neurooncol. 2007, 83, 145–152.
[83]
Pages, F.; Berger, A.; Camus, M.; Sanchez-Cabo, F.; Costes, A.; Molidor, R.; Mlecnik, B.; Kirilovsky, A.; Nilsson, M.; Damotte, D.; Meatchi, T.; Bruneval, P.; Cugnenc, P.H.; Trajanoski, Z.; Fridman, W.H.; Galon, J. Effector memory t cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 2005, 353, 2654–2666.
[84]
Galon, J.; Costes, A.; Sanchez-Cabo, F.; Kirilovsky, A.; Mlecnik, B.; Lagorce-Pages, C.; Tosolini, M.; Camus, M.; Berger, A.; Wind, P.; Zinzindohoue, F.; Bruneval, P.; Cugnenc, P.H.; Trajanoski, Z.; Fridman, W.H.; Pages, F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313, 1960–1964.
[85]
Zisman, T.L.; Rubin, D.T. Colorectal cancer and dysplasia in inflammatory bowel disease. World J. Gastroenterol. 2008, 14, 2662–2669.
[86]
Smalley, W.E.; DuBois, R.N. Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv. Pharmacol. 1997, 39, 1–20.
[87]
Bromberg, J.; Wang, T.C. Inflammation and cancer: Il-6 and stat3 complete the link. Cancer Cell 2009, 15, 79–80.
[88]
Belkaid, Y.; Rouse, B.T. Natural regulatory t cells in infectious disease. Nat. Immunol. 2005, 6, 353–360.
[89]
Sather, B.D.; Treuting, P.; Perdue, N.; Miazgowicz, M.; Fontenot, J.D.; Rudensky, A.Y.; Campbell, D.J. Altering the distribution of foxp3(+) regulatory t cells results in tissue-specific inflammatory disease. J. Exp. Med. 2007, 204, 1335–1347.
[90]
Makita, S.; Kanai, T.; Oshima, S.; Uraushihara, K.; Totsuka, T.; Sawada, T.; Nakamura, T.; Koganei, K.; Fukushima, T.; Watanabe, M. Cd4+cd25bright t cells in human intestinal lamina propria as regulatory cells. J. Immunol. 2004, 173, 3119–3130.
[91]
Holmen, N.; Lundgren, A.; Lundin, S.; Bergin, A.M.; Rudin, A.; Sjovall, H.; Ohman, L. Functional cd4+cd25high regulatory t cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm. Bowel Dis. 2006, 12, 447–456.
[92]
Anz, D.; Mueller, W.; Golic, M.; Kunz, W.G.; Rapp, M.; Koelzer, V.H.; Ellermeier, J.; Ellwart, J.W.; Schnurr, M.; Bourquin, C.; Endres, S. Cd103 is a hallmark of tumor-infiltrating regulatory t cells. Int. J. Cancer 2011, doi:10.1002/ijc.25902.
[93]
Erdman, S.E.; Poutahidis, T. Roles for inflammation and regulatory t cells in colon cancer. Toxicol. Pathol. 2010, 38, 76–87.
Gounaris, E.; Blatner, N.R.; Dennis, K.; Magnusson, F.; Gurish, M.F.; Strom, T.B.; Beckhove, P.; Gounari, F.; Khazaie, K. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res. 2009, 69, 5490–5497.
[105]
Blatner, N.R.; Bonertz, A.; Beckhove, P.; Cheon, E.C.; Krantz, S.B.; Strouch, M.; Weitz, J.; Koch, M.; Halverson, A.L.; Bentrem, D.J.; Khazaie, K. In colorectal cancer mast cells contribute to systemic regulatory t-cell dysfunction. Proc. Natl. Acad. Sci. USA 2010, 107, 6430–6435.
[106]
Somasundaram, R.; Jacob, L.; Swoboda, R.; Caputo, L.; Song, H.; Basak, S.; Monos, D.; Peritt, D.; Marincola, F.; Cai, D.; Birebent, B.; Bloome, E.; Kim, J.; Berencsi, K.; Mastrangelo, M.; Herlyn, D. Inhibition of cytolytic t lymphocyte proliferation by autologous cd4+/cd25+ regulatory t cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res. 2002, 62, 5267–5272.
[107]
Wolf, A.M.; Wolf, D.; Steurer, M.; Gastl, G.; Gunsilius, E.; Grubeck-Loebenstein, B. Increase of regulatory t cells in the peripheral blood of cancer patients. Clin. Cancer Res. 2003, 9, 606–612.
[108]
Ling, K.L.; Pratap, S.E.; Bates, G.J.; Singh, B.; Mortensen, N.J.; George, B.D.; Warren, B.F.; Piris, J.; Roncador, G.; Fox, S.B.; Banham, A.H.; Cerundolo, V. Increased frequency of regulatory t cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun. 2007, 7, 7.
[109]
Correale, P.; Cusi, M.G.; Tsang, K.Y.; Del Vecchio, M.T.; Marsili, S.; Placa, M.L.; Intrivici, C.; Aquino, A.; Micheli, L.; Nencini, C.; Ferrari, F.; Giorgi, G.; Bonmassar, E.; Francini, G. Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus folfox 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J. Clin. Oncol. 2005, 23, 8950–8958.
[110]
Clarke, S.L.; Betts, G.J.; Plant, A.; Wright, K.L.; El-Shanawany, T.M.; Harrop, R.; Torkington, J.; Rees, B.I.; Williams, G.T.; Gallimore, A.M.; Godkin, A.J. Cd4+cd25+foxp3+ regulatory t cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 2006, 1, e129.
[111]
Chaput, N.; Louafi, S.; Bardier, A.; Charlotte, F.; Vaillant, J.C.; Menegaux, F.; Rosenzwajg, M.; Lemoine, F.; Klatzmann, D.; Taieb, J. Identification of cd8+cd25+foxp3+ suppressive t cells in colorectal cancer tissue. Gut 2009, 58, 520–529.
[112]
Loddenkemper, C.; Schernus, M.; Noutsias, M.; Stein, H.; Thiel, E.; Nagorsen, D. In situ analysis of foxp3+ regulatory t cells in human colorectal cancer. J. Transl. Med. 2006, 4, 52.
[113]
Nagorsen, D.; Voigt, S.; Berg, E.; Stein, H.; Thiel, E.; Loddenkemper, C. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: Relation to local regulatory t cells, systemic t-cell response against tumor-associated antigens and survival. J. Transl. Med. 2007, 5, 62.
[114]
Bonertz, A.; Weitz, J.; Pietsch, D.H.; Rahbari, N.N.; Schlude, C.; Ge, Y.; Juenger, S.; Vlodavsky, I.; Khazaie, K.; Jaeger, D.; Reissfelder, C.; Antolovic, D.; Aigner, M.; Koch, M.; Beckhove, P. Antigen-specific tregs control t cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J. Clin. Invest. 2009, 119, 3311–3321.
[115]
Bueter, M.; Gasser, M.; Schramm, N.; Lebedeva, T.; Tocco, G.; Gerstlauer, C.; Grimm, M.; Nichiporuk, E.; Thalheimer, A.; Thiede, A.; Meyer, D.; Benichou, G.; Waaga-Gasser, A.M. T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma. Int. J. Oncol. 2006, 28, 431–438.
[116]
Yang, S.; Wang, B.; Guan, C.; Wu, B.; Cai, C.; Wang, M.; Zhang, B.; Liu, T.; Yang, P. Foxp3+il-17+ t cells promote development of cancer-initiating cells in colorectal cancer. J. Leukoc. Biol. 2011, 89, 85–91.
[117]
Gryfe, R.; Kim, H.; Hsieh, E.T.; Aronson, M.D.; Holowaty, E.J.; Bull, S.B.; Redston, M.; Gallinger, S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N. Engl. J. Med. 2000, 342, 69–77.
[118]
Michel, S.; Benner, A.; Tariverdian, M.; Wentzensen, N.; Hoefler, P.; Pommerencke, T.; Grabe, N.; von Knebel Doeberitz, M.; Kloor, M. High density of foxp3-positive t cells infiltrating colorectal cancers with microsatellite instability. Br. J. Cancer 2008, 99, 1867–1873.
[119]
Sinicrope, F.A.; Rego, R.L.; Ansell, S.M.; Knutson, K.L.; Foster, N.R.; Sargent, D.J. Intraepithelial effector (cd3+)/regulatory (foxp3+) t-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009, 137, 1270–1279.
[120]
Nosho, K.; Baba, Y.; Tanaka, N.; Shima, K.; Hayashi, M.; Meyerhardt, J.A.; Giovannucci, E.; Dranoff, G.; Fuchs, C.S.; Ogino, S. Tumour-infiltrating t-cell subsets, molecular changes in colorectal cancer, and prognosis: Cohort study and literature review. J. Pathol. 2010, 222, 350–366.
[121]
Le Gouvello, S.; Bastuji-Garin, S.; Aloulou, N.; Mansour, H.; Chaumette, M.T.; Berrehar, F.; Seikour, A.; Charachon, A.; Karoui, M.; Leroy, K.; Farcet, J.P.; Sobhani, I. High prevalence of foxp3 and il17 in mmr-proficient colorectal carcinomas. Gut 2008, 57, 772–779.
[122]
Pillai, V.; Karandikar, N.J. Attack on the clones? Human foxp3 detection by pch101, 236a/e7, 206d, and 259d reveals 259d as the outlier with lower sensitivity. Blood 2003, 111, . author reply.
[123]
Woo, Y.L.; Sterling, J.; Crawford, R.; van der Burg, S.H.; Coleman, N.; Stanley, M. Foxp3 immunohistochemistry on formalin-fixed paraffin-embedded tissue: Poor correlation between different antibodies. J. Clin. Pathol. 2008, 61, 969–971.
[124]
Salama, P.; Phillips, M.; Grieu, F.; Morris, M.; Zeps, N.; Joseph, D.; Platell, C.; Iacopetta, B. Tumor-infiltrating foxp3+ t regulatory cells show strong prognostic significance in colorectal cancer. J. Clin. Oncol. 2009, 27, 186–192.
[125]
Erdman, S.E.; Rao, V.P.; Poutahidis, T.; Ihrig, M.M.; Ge, Z.; Feng, Y.; Tomczak, M.; Rogers, A.B.; Horwitz, B.H.; Fox, J.G. Cd4(+)cd25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 2003, 63, 6042–6050.
[126]
Frey, D.M.; Droeser, R.A.; Viehl, C.T.; Zlobec, I.; Lugli, A.; Zingg, U.; Oertli, D.; Kettelhack, C.; Terracciano, L.; Tornillo, L. High frequency of tumor-infiltrating foxp3(+) regulatory t cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int. J. Cancer 2010, 126, 2635–2643.
[127]
Correale, P.; Rotundo, M.S.; Del Vecchio, M.T.; Remondo, C.; Migali, C.; Ginanneschi, C.; Tsang, K.Y.; Licchetta, A.; Mannucci, S.; Loiacono, L.; Tassone, P.; Francini, G.; Tagliaferri, P. Regulatory (foxp3+) t-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J. Immunother. 2010, 33, 435–441.
[128]
Suzuki, H.; Chikazawa, N.; Tasaka, T.; Wada, J.; Yamasaki, A.; Kitaura, Y.; Sozaki, M.; Tanaka, M.; Onishi, H.; Morisaki, T.; Katano, M. Intratumoral cd8(+) t/foxp3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol. Immunother. 2010, 59, 653–661.
[129]
Deng, L.; Zhang, H.; Luan, Y.; Zhang, J.; Xing, Q.; Dong, S.; Wu, X.; Liu, M.; Wang, S. Accumulation of foxp3+ t regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin. Cancer Res. 2010, 16, 4105–4112.
[130]
Matera, L.; Sandrucci, S.; Mussa, A.; Boffa, C.; Castellano, I.; Cassoni, P. Low foxp3 expression in negative sentinel lymph nodes is associated with node metastases in colorectal cancer. Gut 2010, 59, 419–420.
[131]
Saha, A.; Chatterjee, S.K. 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. 2010, 71, 70–82.
[132]
Colombo, M.P.; Piconese, S. Regulatory-t-cell inhibition versus depletion: The right choice in cancer immunotherapy. Nat. Rev. Cancer 2007, 7, 880–887.
[133]
Ghiringhelli, F.; Menard, C.; Puig, P.E.; Ladoire, S.; Roux, S.; Martin, F.; Solary, E.; Le Cesne, A.; Zitvogel, L.; Chauffert, B. Metronomic cyclophosphamide regimen selectively depletes cd4+cd25+ regulatory t cells and restores t and nk effector functions in end stage cancer patients. Cancer Immunol. Immunother. 2007, 56, 641–648.
[134]
Audia, S.; Nicolas, A.; Cathelin, D.; Larmonier, N.; Ferrand, C.; Foucher, P.; Fanton, A.; Bergoin, E.; Maynadie, M.; Arnould, L.; Bateman, A.; Lorcerie, B.; Solary, E.; Chauffert, B.; Bonnotte, B. Increase of cd4+ cd25+ regulatory t cells in the peripheral blood of patients with metastatic carcinoma: A phase i clinical trial using cyclophosphamide and immunotherapy to eliminate cd4+ cd25+ t lymphocytes. Clin. Exp. Immunol. 2007, 150, 523–530.
[135]
Dannull, J.; Su, Z.; Rizzieri, D.; Yang, B.K.; Coleman, D.; Yancey, D.; Zhang, A.; Dahm, P.; Chao, N.; Gilboa, E.; Vieweg, J. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory t cells. J. Clin. Invest. 2005, 115, 3623–3633.
[136]
Morse, M.A.; Hobeika, A.C.; Osada, T.; Serra, D.; Niedzwiecki, D.; Lyerly, H.K.; Clay, T.M. Depletion of human regulatory t cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 2008, 112, 610–618.
[137]
Okita, R.; Yamaguchi, Y.; Ohara, M.; Hironaka, K.; Okawaki, M.; Nagamine, I.; Ikeda, T.; Emi, A.; Hihara, J.; Okada, M. Targeting of cd4+cd25high cells while preserving cd4+cd25low cells with low-dose chimeric anti-cd25 antibody in adoptive immunotherapy of cancer. Int. J. Oncol. 2009, 34, 563–572.
[138]
Rech, A.J.; Vonderheide, R.H. Clinical use of anti-cd25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory t cells. Ann. N. Y. Acad. Sci. 2009, 1174, 99–106.
[139]
Egen, J.G.; Kuhns, M.S.; Allison, J.P. Ctla-4: New insights into its biological function and use in tumor immunotherapy. Nat. Immunol. 2002, 3, 611–618.
[140]
Takahashi, T.; Tagami, T.; Yamazaki, S.; Uede, T.; Shimizu, J.; Sakaguchi, N.; Mak, T.W.; Sakaguchi, S. Immunologic self-tolerance maintained by cd25(+)cd4(+) regulatory t cells constitutively expressing cytotoxic t lymphocyte-associated antigen 4. J. Exp. Med. 2000, 192, 303–310.
[141]
Liakou, C.I.; Kamat, A.; Tang, D.N.; Chen, H.; Sun, J.; Troncoso, P.; Logothetis, C.; Sharma, P. Ctla-4 blockade increases ifngamma-producing cd4+icoshi cells to shift the ratio of effector to regulatory t cells in cancer patients. Proc. Natl. Acad. Sci. USA 2008, 105, 14987–14992.
[142]
Yuan, J.; Gnjatic, S.; Li, H.; Powel, S.; Gallardo, H.F.; Ritter, E.; Ku, G.Y.; Jungbluth, A.A.; Segal, N.H.; Rasalan, T.S.; Manukian, G.; Xu, Y.; Roman, R.A.; Terzulli, S.L.; Heywood, M.; Pogoriler, E.; Ritter, G.; Old, L.J.; Allison, J.P.; Wolchok, J.D. Ctla-4 blockade enhances polyfunctional ny-eso-1 specific t cell responses in metastatic melanoma patients with clinical benefit. Proc. Natl. Acad. Sci. USA 2008, 105, 20410–20415.
[143]
Nyirenda, M.H.; O'Brien, K.; Sanvito, L.; Constantinescu, C.S.; Gran, B. Modulation of regulatory t cells in health and disease: Role of toll-like receptors. Inflamm. Allergy Drug Target 2009, 8, 124–129.
