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T regulatory cells in cancer: recent advances and therapeutic potential

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Pages 1573-1586 | Published online: 19 Oct 2010

Bibliography

  • Talmadge JE. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 2007;13:5243-8
  • Dunn GP, Bruce AT, Ikeda H, Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991-8
  • Takahashi T, Sakaguchi S. Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease. Curr Mol Med 2003;3:693-706
  • Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009;30:626-35
  • Sakaguchi S, Sakaguchi N, Asano 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;155:1151-64
  • Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6
  • Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-61
  • Ouyang W, Beckett O, Ma Q, Li MO. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 2010;32:642-53
  • Chen W, Jin W, Hardegen N, 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;198:1875-86
  • Roncarolo MG, Gregori S, Battaglia M, Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006;212:28-50
  • Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001;182:207-14
  • Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003;3:253-7
  • Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009;30:636-45
  • Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 2008;9:239-44
  • Sakaguchi S, Wing K, Onishi Y, Regulatory T cells: how do they suppress immune responses? Int Immunol 2009;21:1105-11
  • Zhou G, Levitsky HI. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 2007;178:2155-62
  • Chaput N, Louafi S, Bardier A, Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 2009;58:520-9
  • Andersen MH, Sorensen RB, Brimnes MK, Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients. J Clin Invest 2009;119:2245-56
  • Curiel TJ, Coukos G, Zou L, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-9
  • Griffiths RW, Elkord E, Gilham DE, Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 2007;56:1743-53
  • Wolf AM, Wolf D, Steurer M, Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003;9:606-12
  • Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005;5:263-74
  • Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307
  • Skapenko A, Kalden JR, Lipsky PE, Schulze-Koops H. The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors. J Immunol 2005;175:6107-16
  • Valzasina B, Piconese S, Guiducci C, Colombo MP. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25- lymphocytes is thymus and proliferation independent. Cancer Res 2006;66:4488-95
  • Chattopadhyay S, Mehrotra S, Chhabra A, Effect of CD4+CD25+ and CD4+CD25- T regulatory cells on the generation of cytolytic T cell response to a self but human tumor-associated epitope in vitro. J Immunol 2006;176:984-90
  • Smyth GP, Stapleton PP, Barden CB, Renal cell carcinoma induces prostaglandin E2 and T-helper type 2 cytokine production in peripheral blood mononuclear cells. Ann Surg Oncol 2003;10:455-62
  • Na X, Wu G, Ryan CK, Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. J Urol 2003;170:588-92
  • Gomella LG, Sargent ER, Wade TP, Expression of transforming growth factor alpha in normal human adult kidney and enhanced expression of transforming growth factors alpha and beta 1 in renal cell carcinoma. Cancer Res 1989;49:6972-5
  • Bergmann C, Strauss L, Zeidler R, Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 2007;67:8865-73
  • Akasaki Y, Liu G, Chung NH, Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 2004;173:4352-9
  • Lee I, Wang L, Wells AD, Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 2005;201:1037-44
  • Jeron A, Pfoertner S, Bruder D, Frequency and gene expression profile of regulatory T cells in renal cell carcinoma. Tumour Biol 2009;30:160-70
  • Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opin Immunol 2007;19:217-23
  • Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol 2008;20:241-6
  • Samy ET, Parker LA, Sharp CP, Tung KS. Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J Exp Med 2005;202:771-81
  • Tarbell KV, Yamazaki S, Olson K, CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004;199:1467-77
  • Wang HY, Lee DA, Peng G, Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 2004;20:107-18
  • Wang HY, Peng G, Guo Z, Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol 2005;174:2661-70
  • Voo KS, Peng G, Guo Z, Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation. Cancer Res 2005;65:1577-86
  • Bonertz A, Weitz J, Pietsch DH, Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 2009;119:3311-21
  • Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-74
  • Marigo I, Dolcetti L, Serafini P, Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 2008;222:162-79
  • Zea AH, Rodriguez PC, Atkins MB, Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005;65:3044-8
  • Hoechst B, Ormandy LA, Ballmaier M, A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008;135:234-43
  • Diaz-Montero CM, Salem ML, Nishimura MI, Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009;58:49-59
  • Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004;172:989-99
  • Pan PY, Ma G, Weber KJ, 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 2010;70:99-108
  • Sugimoto N, Oida T, Hirota K, Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 2006;18:1197-209
  • Liu W, Putnam AL, Xu-Yu Z, CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-11
  • Seddiki N, Santner-Nanan B, Martinson J, Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693-700
  • Thornton AM, Korty PE, Tran DQ, Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010;184:3433-41
  • Huang CT, Workman CJ, Flies D, Role of LAG-3 in regulatory T cells. Immunity 2004;21:503-13
  • Camisaschi C, Casati C, Rini F, LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 2010;184:6545-51
  • Dong C, Juedes AE, Temann UA, ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 2001;409:97-101
  • Chen X, Subleski JJ, Kopf H, Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol 2008;180:6467-71
  • Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004;199:1479-89
  • Strauss L, Bergmann C, Szczepanski MJ, Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression. J Immunol 2008;180:2967-80
  • Ito T, Hanabuchi S, Wang YH, Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 2008;28:870-80
  • Chen X, Subleski JJ, Hamano R, Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. Eur J Immunol 2010;40:1099-106
  • Chen ML, Yan BS, Bando Y, Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFbeta-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J Immunol 2008;180:7327-37
  • Tran DQ, Andersson J, Hardwick D, 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;113:5125-33
  • Stockis J, Colau D, Coulie PG, Lucas S. Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg. Eur J Immunol 2009;39:3315-22
  • Tran DQ, Andersson J, Wang R, GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13445-50
  • Wang R, Kozhaya L, Mercer F, Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13439-44
  • Martinez-Cardus A, Martinez-Balibrea E, Bandres E, Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer. Mol Cancer Ther 2009;8:194-202
  • Miyara M, Yoshioka Y, Kitoh A, Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911
  • Daayana S, Elkord E, Winters U, Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia. Br J Cancer;102:1129-36
  • Elkord E, Dangoor A, Burt DJ, Immune evasion mechanisms in colorectal cancer liver metastasis patients vaccinated with TroVax (MVA-5T4). Cancer Immunol Immunother 2009;58:1657-67
  • Winters U, Daayana S, Lear JT, Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulval intraepithelial neoplasia. Clin Cancer Res 2008;14:5292-9
  • Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010;127:759-67
  • Needham DJ, Lee JX, Beilharz MW. Intra-tumoural regulatory T cells: a potential new target in cancer immunotherapy. Biochem Biophys Res Commun 2006;343:684-91
  • Zhou Q, Bucher C, Munger ME, Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia. Blood 2009;114:3793-802
  • Nishikawa H, Jager E, Ritter G, CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood 2005;106:1008-11
  • Elkord E, Burt DJ, Drijfhout JW, CD4+ T-cell recognition of human 5T4 oncofoetal antigen: implications for initial depletion of CD25+ T cells. Cancer Immunol Immunother 2008;57:833-47
  • Clarke SL, Betts GJ, Plant A, CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 2006;1:e129
  • Cesana GC, DeRaffele G, Cohen S, Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 2006;24:1169-77
  • Dannull J, Su Z, Rizzieri D, Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005;115:3623-33
  • Thistlethwaite FC, Elkord E, Griffiths RW, Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother 2008;57:623-34
  • Ghiringhelli F, Larmonier N, Schmitt E, CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004;34:336-44
  • Lutsiak ME, Semnani RT, De Pascalis R, Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862-8
  • Beyer M, Kochanek M, Darabi K, Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005;106:2018-25
  • van der Most RG, Currie AJ, Mahendran S, 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 2009;58:1219-28
  • Onizuka S, Tawara I, Shimizu J, Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128-33
  • Golgher D, Jones E, Powrie F, Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 2002;32:3267-75
  • Litzinger MT, Fernando R, Curiel TJ, IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 2007;110:3192-201
  • Mahnke K, Schonfeld K, Fondel S, Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int J Cancer 2007;120:2723-33
  • Attia P, Maker AV, Haworth LR, Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 2005;28:582-92
  • Powell DJ Jr, Felipe-Silva A, Merino MJ, Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J Immunol 2007;179:4919-28
  • Powell DJ Jr, de Vries CR, Allen T, Inability to mediate prolonged reduction of regulatory T Cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy. J Immunother 2007;30:438-47
  • Oh U, Blevins G, Griffith C, Regulatory T cells are reduced during anti-CD25 antibody treatment of multiple sclerosis. Arch Neurol 2009;66:471-9
  • Rech AJ, Vonderheide RH. 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
  • Hodi FS, O'Day SJ, McDermott DF, Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23
  • Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005;175:7746-54
  • Kavanagh B, O'Brien S, Lee D, CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 2008;112:1175-83
  • Ralph C, Elkord E, Burt DJ, Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res;16:1662-72
  • Shevach EM, Stephens GL. The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat Rev Immunol 2006;6:613-18
  • Cohen AD, Diab A, Perales MA, Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res 2006;66:4904-12
  • Mitsui J, Nishikawa H, Muraoka D, Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res 2010;16:2781-91
  • Raimondi G, Shufesky WJ, Tokita D, Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells. J Immunol 2006;176:2808-16
  • Dai H, Wan N, Zhang S, Cutting edge: programmed Death-1 defines CD8+ CD122+ T cells as regulatory versus memory T cells. J Immunol 2010;185:803-7
  • Zhou Q, Munger ME, Highfill SL, Program death-1 (PD-1) signaling and regulatory T cells (Tregs) collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes (CTLs) in advanced acute myeloid leukemia (AML). Blood 2010
  • Brahmer JR, Drake CG, Wollner I, Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-75
  • Sznol M, Powderly JD, Smith DC, Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies (abstract 2506). J Clin Oncol 2010;28(Suppl):15s
  • Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048-53
  • Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 2008;205:825-39
  • Yamaguchi T, Hirota K, Nagahama K, Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 2007;27:145-59
  • Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother 2007;56:271-85
  • Walker MR, Kasprowicz DJ, Gersuk VH, Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J Clin Invest 2003;112:1437-43
  • Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007;110:2983-90
  • Wang J, Ioan-Facsinay A, van der Voort EI, Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007;37:129-38
  • Kryczek I, Liu R, Wang G, FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res 2009;69:3995-4000
  • Zitvogel L, Apetoh L, Ghiringhelli F, The anticancer immune response: indispensable for therapeutic success? J Clin Invest 2008;118:1991-2001
  • Iellem A, Mariani M, Lang R, Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 2001;194:847-53
  • Mizukami Y, Kono K, Kawaguchi Y, CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer 2008;122:2286-93
  • Kang S, Xie J, Ma S, Targeted knock down of CCL22 and CCL17 by siRNA during DC differentiation and maturation affects the recruitment of T subsets. Immunobiology 2010;215:153-62
  • Curti A, Pandolfi S, Valzasina B, Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25 – into CD25+ T regulatory cells. Blood 2007;109:2871-7
  • Beyer M, Schultze JL. Immunoregulatory T cells: role and potential as a target in malignancy. Curr Oncol Rep 2008;10:130-6
  • Vence L, Palucka AK, Fay JW, Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci USA 2007;104:20884-9
  • Zhou G, Drake CG, Levitsky HI. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 2006;107:628-36
  • Nair S, Boczkowski D, Fassnacht M, Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 2007;67:371-80
  • Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer 2007;7:880-7
  • Xu L, Xu W, Qiu S, Xiong S. Enrichment of CCR6+Foxp3+ regulatory T cells in the tumor mass correlates with impaired CD8+ T cell function and poor prognosis of breast cancer. Clin Immunol 2010;135:466-75
  • Bates GJ, Fox SB, Han C, Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006;24:5373-80
  • Merlo A, Casalini P, Carcangiu ML, FOXP3 expression and overall survival in breast cancer. J Clin Oncol 2009;27:1746-52
  • Wolf D, Wolf AM, Rumpold H, The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005;11:8326-31
  • Correale P, Rotundo MS, Del Vecchio MT, Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010;33:435-41
  • Salama P, Phillips M, Grieu F, Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186-92
  • Deng L, Zhang H, Luan Y, 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;16:4105-12
  • Grabenbauer GG, Lahmer G, Distel L, Niedobitek G. Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 2006;12:3355-60
  • Jensen HK, Donskov F, Nordsmark M, Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. Clin Cancer Res 2009;15:1052-8
  • de Jong RA, Leffers N, Boezen HM, Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 2009;114:105-10
  • Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006;12:5423-34
  • Perrone G, Ruffini PA, Catalano V, Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 2008;44:1875-82
  • Carreras J, Lopez-Guillermo A, Fox BC, High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 2006;108:2957-64
  • Farinha P, Al-Tourah A, Gill K, The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood 2010;115:289-95
  • Li JF, Chu YW, Wang GM, The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int 2009;103:399-405
  • Sato E, Olson SH, Ahn J, 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 USA 2005;102:18538-43
  • Suzuki H, Chikazawa N, Tasaka T, Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61
  • Loddenkemper C, Schernus M, Noutsias M, In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer. J Transl Med 2006;4:52
  • Gao Q, Qiu SJ, Fan J, Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586-93
  • Fu J, Xu D, Liu Z, Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-39

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