Abstract
In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that–in the vast majority of cases–express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3+ regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4+ cells. The prognostic/predictive significance of tumor infiltration by Tregs remains a matter of debate. Indeed, high levels of intratumoral Tregs have been associated with poor disease outcome in cohorts of patients affected by multiple, but not all, tumor types. This apparent discrepancy may relate to the existence of functionally distinct Treg subsets, to the fact that Tregs near-to-invariably infiltrate neoplastic lesions together with other cells from the immune system, notably CD4+ and CD8+ T lymphocytes and/or to peculiar features of some oncogenic programs that involve a prominent pro-inflammatory component. In this review, we will discuss the phenotype, function and clinical significance of various Treg subsets.
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Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117
Quezada SA, Peggs KS, Simpson TR, Allison JP (2011) Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication. Immunol Rev 241(1):104–118
Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116(7):1935–1945
Galluzzi L, Senovilla L, Zitvogel L, Kroemer G (2012) The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 11(3):215–233. doi:10.1038/nrd3626
Galluzzi L, Vacchelli E, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zucman-Rossi J et al (2012) Trial Watch: monoclonal antibodies in cancer therapy. Oncoimmunology 1(1):28–37. doi:10.4161/onci.1.1.17938
Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11(2):119–130
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265
Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 30:733–758
Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36(2):262–275. doi:10.1016/j.immuni.2011.12.012
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203(7):1701–1711
Allan SE, Alstad AN, Merindol N, Crellin NK, Amendola M, Bacchetta R, Naldini L et al (2008) Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther 16(1):194–202. doi:10.1038/sj.mt.6300341
Simonetta F, Chiali A, Cordier C, Urrutia A, Girault I, Bloquet S, Tanchot C, Bourgeois C (2010) Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. Eur J Immunol 40(9):2528–2538. doi:10.1002/eji.201040531
Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742
Kawaida H, Kono K, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H et al (2005) Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124(1):151–157. doi:10.1016/j.jss.2004.10.004
Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Fujii H (2006) CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55(9):1064–1071
Han Y, Guo Q, Zhang M, Chen Z, Cao X (2009) CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol 182(1):111–120
Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, Vollmar P et al (2008) IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 105(47):18460–18465. doi:10.1073/pnas.0809850105
Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113(24):6102–6111. doi:10.1182/blood-2008-12-195354
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5(2):e38
Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445(7129):771–775
Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S (2009) Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A 106(6):1903–1908
Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441
Verhagen J, Wraith DC (2010) Comment on “Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells”. J Immunol 185(12):7129, author reply 7130
Akimova T, Beier UH, Wang L, Levine MH, Hancock WW (2011) Helios expression is a marker of T cell activation and proliferation. PLoS One 6(8):e24226
Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8(12):1353–1362
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275
Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL (2007) The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13(21):6301–6311
Whiteside TL (2012) What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol 22(4):327–334
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949
Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C 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):2000–2009
Menetrier-Caux C, Faget J, Biota C, Gobert M, Blay JY, Caux C (2012) Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment. Oncoimmunology 1(5):759–761. doi:10.4161/onci.19680
Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, Lang S et al (2010) Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem 285(10):7176–7186
Mandapathil M, Szczepanski M, Harasymczuk M, Ren J, Cheng D, Jackson EK, Gorelik E et al (2012) CD26 expression and adenosine deaminase activity in regulatory T cells (Treg) and CD4(+) T effector cells in patients with head and neck squamous cell carcinoma. Oncoimmunology 1(5):659–669. doi:10.4161/onci.20387
Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, Sun J, Yang Q, Zhang X, Lu B (2012) TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 7(2):e30676
Pere H, Montier Y, Bayry J, Quintin-Colonna F, Merillon N, Dransart E, Badoual C et al (2011) A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood 118(18):4853–4862
van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA (2009) Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58(8):1219–1228. doi:10.1007/s00262-008-0628-9
Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D'Ambrosio D (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 194(6):847–853
Wei S, Kryczek I, Zou W (2006) Regulatory T-cell compartmentalization and trafficking. Blood 108(2):426–431
Pere H, Tanchot C, Bayry J, Terme M, Taieb J, Badoual C, Adotevi O et al (2012) Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer. Oncoimmunology 1(3):326–333. doi:10.4161/onci.18852
Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470(7335):548–553
Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M, Cost M et al (2007) Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 67(15):7487–7494
Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M, Moons L et al (2005) CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 65(2):465–472
Jaafar F, Righi E, Lindstrom V, Linton C, Nohadani M, Van Noorden S, Lloyd T et al (2009) Correlation of CXCL12 expression and FoxP3+ cell infiltration with human papillomavirus infection and clinicopathological progression of cervical cancer. Am J Pathol 175(4):1525–1535
Wang C, Lee JH, Kim CH (2012) Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch. PLoS One 7(1):e30793
Nizar S, Meyer B, Galustian C, Kumar D, Dalgleish A (2010) T regulatory cells, the evolution of targeted immunotherapy. Biochim Biophys Acta 1806(1):7–17
Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99–108
Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449
Quezada SA, Peggs KS, Simpson TR, Shen Y, Littman DR, Allison JP (2008) Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 205(9):2125–2138
Brody JR, Costantino CL, Berger AC, Sato T, Lisanti MP, Yeo CJ, Emmons RV, Witkiewicz AK (2009) Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8(12):1930–1934
Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183(4):2475–2483. doi:10.4049/jimmunol.0900986
Chung DJ, Rossi M, Romano E, Ghith J, Yuan J, Munn DH, Young JW (2009) Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood 114(3):555–563
Croci DO, Zacarias Fluck MF, Rico MJ, Matar P, Rabinovich GA, Scharovsky OG (2007) Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunother 56(11):1687–1700
Mehrotra S, Mougiakakos D, Johansson CC, Voelkel-Johnson C, Kiessling R (2009) Oxidative stress and lymphocyte persistence: implications in immunotherapy. Adv Cancer Res 102:197–227
Mougiakakos D, Johansson CC, Kiessling R (2009) Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 113(15):3542–3545
Kuczma M, Kopij M, Pawlikowska I, Wang CY, Rempala GA, Kraj P (2010) Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells. PLoS One 5(10):e13623
Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, Zhang Q 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):2883–2892
Schreiber TH, Wolf D, Bodero M, Podack E (2012) Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. Oncoimmunology 1(5):642–648. doi:10.4161/onci.20298
Valzasina B, Piconese S, Guiducci C, Colombo MP (2006) Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25- lymphocytes is thymus and proliferation independent. Cancer Res 66(8):4488–4495
Zhou G, Levitsky HI (2007) Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 178(4):2155–2162
Elkord E, Sharma S, Burt DJ, Hawkins RE (2011) Expanded subpopulation of FoxP3+ T regulatory cells in renal cell carcinoma co-express Helios, indicating they could be derived from natural but not induced Tregs. Clin Immunol 140(3):218–222
Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G et al (2005) Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202(7):919–929
Hindley JP, Ferreira C, Jones E, Lauder SN, Ladell K, Wynn KK, Betts GJ et al (2011) Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 71(3):736–746
Sainz-Perez A, Lim A, Lemercier B, Leclerc C (2012) The T-cell receptor repertoire of tumor-infiltrating regulatory T lymphocytes is skewed toward public sequences. Cancer Res 72(14):3557–3569
Facciabene A, Santoro S, Coukos G (2012) Know thy enemy: why are tumor-infiltrating regulatory T cells so deleterious? Oncoimmunology 1(4):575–577
Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475(7355):226–230
Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38(9):2412–2418. doi:10.1002/eji.200838318
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096–1103
Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F et al (2011) Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30(1):83–95. doi:10.1007/s10555-011-9281-4
Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M (2010) VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 40(1):197–203. doi:10.1002/eji.200939887
Motz GT, Coukos G (2011) The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol 11(10):702–711
Giatromanolaki A, Bates GJ, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, Banham AH (2008) The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol 110(2):216–221. doi:10.1016/j.ygyno.2008.04.021
Gupta S, Joshi K, Wig JD, Arora SK (2007) Intratumoral FOXP3 expression in infiltrating breast carcinoma: its association with clinicopathologic parameters and angiogenesis. Acta Oncol 46(6):792–797. doi:10.1080/02841860701233443
Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, Medioni J et al (2010) A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33(9):991–998. doi:10.1097/CJI.0b013e3181f4c208
Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L et al (2008) Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 14(20):6674–6682. doi:10.1158/1078-0432.CCR-07-5212
Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, Weinschenk T et al (2008) Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 111(12):5610–5620. doi:10.1182/blood-2007-02-075945
Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M et al (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69(6):2514–2522. doi:10.1158/0008-5472.CAN-08-4709
Busse A, Asemissen AM, Nonnenmacher A, Braun F, Ochsenreither S, Stather D, Fusi A et al (2011) Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma. Eur J Cancer 47(5):690–696. doi:10.1016/j.ejca.2010.11.021
Cao M, Xu Y, Youn JI, Cabrera R, Zhang X, Gabrilovich D, Nelson DR, Liu C (2011) Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Investig 91(4):598–608
Florcken A, Takvorian A, Van Lessen A, Singh A, Hopfenmuller W, Dorken B, Pezzutto A, Westermann J (2011) Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma. Anticancer Drugs. doi:10.1097/CAD.0b013e32834ee2b1
Nagai H, Mukozu T, Matsui D, Kanekawa T, Kanayama M, Wakui N, Momiyama K et al (2012) Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma. Clin Dev Immunol 2012:607851
Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P et al (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7(1):83–92. doi:10.1038/ni1289
Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM (2004) CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199(11):1467–1477. doi:10.1084/jem.20040180
Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, Shevach EM, Wang RF (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20(1):107–118
Wang HY, Peng G, Guo Z, Shevach EM, Wang RF (2005) Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol 174(5):2661–2670
Vence L, Palucka AK, Fay JW, Ito T, Liu YJ, Banchereau J, Ueno H (2007) Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci U S A 104(52):20884–20889. doi:10.1073/pnas.0710557105
Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S et al (2009) Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 119(11):3311–3321
Zhou G, Drake CG, Levitsky HI (2006) Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107(2):628–636
Francois V, Ottaviani S, Renkvist N, Stockis J, Schuler G, Thielemans K, Colau D et al (2009) The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells. Cancer Res 69(10):4335–4345
Welters MJ, Kenter GG, Piersma SJ, Vloon AP, Lowik MJ, Berends-van der Meer DM, Drijfhout JW et al (2008) Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res 14(1):178–187. doi:10.1158/1078-0432.CCR-07-1880
Welters MJ, Kenter GG, de Vos van Steenwijk PJ, Lowik MJ, Berends-van der Meer DM, Essahsah F, Stynenbosch LF et al (2010) Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc Natl Acad Sci U S A 107(26):11895–11899
Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, Mosseri V et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12(2):465–472
Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (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(34):5373–5380
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102(51):18538–18543
Schneider T, Kimpfler S, Warth A, Schnabel PA, Dienemann H, Schadendorf D, Hoffmann H, Umansky V (2011) Foxp3(+) regulatory T cells and natural killer cells distinctly infiltrate primary tumors and draining lymph nodes in pulmonary adenocarcinoma. J Thorac Oncol 6(3):432–438
Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, Fumoleau P, Ghiringhelli F (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14(8):2413–2420
Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC et al (2011) Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 17(9):1094–1100. doi:10.1038/nm.2438
Badoual C, Sandoval F, Pere H, Hans S, Gey A, Merillon N, Van Ryswick C et al (2010) Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies. Head Neck 32(7):946–958. doi:10.1002/hed.21346
Bron L, Jandus C, Andrejevic-Blant S, Speiser DE, Monnier P, Romero P, Rivals JP (2012) Prognostic value of arginase-II expression and regulatory T cell infiltration in head and neck squamous cell carcinoma. Int J Cancer. doi:10.1002/ijc.27728
Loose D, Van de Wiele C (2009) The immune system and cancer. Cancer Biother Radiopharm 24(3):369–376. doi:10.1089/cbr.2008.0593
Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D et al (2010) High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 126(11):2635–2643. doi:10.1002/ijc.24989
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27(2):186–192
Winerdal ME, Marits P, Winerdal M, Hasan M, Rosenblatt R, Tolf A, Selling K, Sherif A, Winqvist O (2011) FOXP3 and survival in urinary bladder cancer. BJU Int 108(10):1672–1678. doi:10.1111/j.1464-410X.2010.10020.x
Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, Montserrat E et al (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108(9):2957–2964
deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18(11):3022–3029. doi:10.1158/1078-0432.CCR-11-3216
Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E et al (2011) IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 186(7):4388–4395. doi:10.4049/jimmunol.1003251
Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunsi K, Valmori D, Ayyoub M (2012) CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res 72(17):4351–4360. doi:10.1158/0008-5472.CAN-12-0579
Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K (2010) Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109(5):744–752
McCluggage WG, Walsh MY, Bharucha H (1998) Anaplastic large cell malignant lymphoma with extensive eosinophilic or neutrophilic infiltration. Histopathology 32(2):110–115
Badoual C, Bouchaud G, Agueznay Nel H, Mortier E, Hans S, Gey A, Fernani F et al (2008) The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res 68(10):3907–3914
Tartour E, Mosseri V, Jouffroy T, Deneux L, Jaulerry C, Brunin F, Fridman WH, Rodriguez J (2001) Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet 357(9264):1263–1264
Haas M, Dimmler A, Hohenberger W, Grabenbauer GG, Niedobitek G, Distel LV (2009) Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 9:65. doi:10.1186/1471-230X-9-65
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15(2):103–113
Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G (2011) Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 71(17):5601–5605. doi:10.1158/0008-5472.CAN-11-1316
Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. doi:10.1038/nrc3245
Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25(18):2586–2593. doi:10.1200/JCO.2006.09.4565
Distel LV, Fickenscher R, Dietel K, Hung A, Iro H, Zenk J, Nkenke E, Buttner M, Niedobitek G, Grabenbauer GG (2009) Tumour infiltrating lymphocytes in squamous cell carcinoma of the oro- and hypopharynx: prognostic impact may depend on type of treatment and stage of disease. Oral Oncol 45(10):e167–e174
Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM et al (2009) Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58(3):449–459. doi:10.1007/s00262-008-0583-5
Acknowledgments
This work was supported by Canceropole Ile de France, ANR (Agence Nationale de la Recherche), Ligue contre le Cancer, Association pour la Recherche sur le Cancer, Institut National du Cancer, Centre d’investigation Clinique en Biothérapie (CIC-BT505), Labex Immuno-Oncology.
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Tanchot, C., Terme, M., Pere, H. et al. Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance. Cancer Microenvironment 6, 147–157 (2013). https://doi.org/10.1007/s12307-012-0122-y
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DOI: https://doi.org/10.1007/s12307-012-0122-y