Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

References

• Piconese S, Timperi E, Pacella I, Schinzari V, Tripodo C, Rossi M, Guglielmo N, Mennini G, Grazi GL, Filippo S et al. Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology 2014; 60:1494-507; PMID:24756990; http://dx.doi.org/10.1002/hep.27188
   PubMed Web of Science ®Google Scholar
• deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 2012; 18:3022-9; PMID:22510350; http://dx.doi.org/10.1158/1078-0432.CCR-11-3216
   PubMed Web of Science ®Google Scholar
• Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011; 60:909-18; PMID:21644034; http://dx.doi.org/10.1007/s00262-011-1046-y
   PubMed Web of Science ®Google Scholar
• 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; 27:186-92; PMID:19064967; http://dx.doi.org/10.1200/JCO.2008.18.7229
   PubMed Web of Science ®Google Scholar
• Gallimore AM, Simon AK. Positive and negative influences of regulatory T cells on tumour immunity. Oncogene 2008; 27:5886-93; PMID:18836469; http://dx.doi.org/10.1038/onc.2008.269
   PubMed Web of Science ®Google Scholar
• Geis AL, Fan H, Wu X, Wu S, Huso DL, Wolfe JL, Sears CL, Pardoll DM, Housseau F. Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis. Cancer Discov 2015; 5:1098-109; PMID:26201900; http://dx.doi.org/10.1158/2159-8290.CD-15-0447
   PubMed Web of Science ®Google Scholar
• Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, Kumar M, Jones S, Rees B, Williams G et al. Suppression of tumour-specific CD4(+) T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 2012; 61:1163-71; PMID:22207629; http://dx.doi.org/10.1136/gutjnl-2011-300970
   PubMed Web of Science ®Google Scholar
• Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D et al. 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; PMID:19809157; http://dx.doi.org/10.1172/JCI39608
   PubMed Web of Science ®Google Scholar
• Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 2006; 1:e129; PMID:17205133; http://dx.doi.org/10.1371/journal.pone.0000129
   PubMed Web of Science ®Google Scholar
• Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313:1960-4; PMID:17008531; http://dx.doi.org/10.1126/science.1129139
   PubMed Web of Science ®Google Scholar
• Di Caro G, Bergomas F, Grizzi F, Doni A, Bianchi P, Malesci A, Laghi L, Allavena P, Mantovani A, Marchesi F. Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin Cancer Res 2014; 20:2147-58; PMID:24523438; http://dx.doi.org/10.1158/1078-0432.CCR-13-2590
   PubMed Web of Science ®Google Scholar
• Sage PT, Sharpe AH. T follicular regulatory cells in the regulation of B cell responses. Trends Immunol 2015; 36:410-8; PMID:26091728; http://dx.doi.org/10.1016/j.it.2015.05.005
   PubMed Web of Science ®Google Scholar
• Blatner NR, Mulcahy MF, Dennis KL, Scholtens D, Bentrem DJ, Phillips JD, Ham S, Sandall BP, Khan MW, Mahvi DM et al. Expression of RORgammat marks a pathogenic regulatory T cell subset in human colon cancer. Sci Transl Med 2012; 4:164ra59; PMID:23241743; http://dx.doi.org/10.1126/scitranslmed.3004566
   Google Scholar
• Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30:899-911; PMID:19464196; http://dx.doi.org/10.1016/j.immuni.2009.03.019
   PubMed Web of Science ®Google Scholar
• Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K et al. Helios Enhances Treg Cell Function in Cooperation With FoxP3. Arthritis Rheumatol 2015; 67:1491-502; PMID:25733061; http://dx.doi.org/10.1002/art.39091
   PubMed Web of Science ®Google Scholar
• Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 2015; 350:334-9; PMID:26472910; http://dx.doi.org/10.1126/science.aad0616
   PubMed Web of Science ®Google Scholar
• Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity 2009; 31:401-11; PMID:19766083; http://dx.doi.org/10.1016/j.immuni.2009.08.011
   PubMed Web of Science ®Google Scholar
• Waight JD, Takai S, Marelli B, Qin G, Hance KW, Zhang D, Tighe R, Lan Y, Lo KM, Sabzevari H et al. Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans. J Immunol 2015; 194:878-82; PMID:25548231; http://dx.doi.org/10.4049/jimmunol.1402725
   PubMed Web of Science ®Google Scholar
• Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med 2010; 207:699-709; PMID:20368580; http://dx.doi.org/10.1084/jem.20091618
   PubMed Web of Science ®Google Scholar
• Piconese S, Pittoni P, Burocchi A, Gorzanelli A, Care A, Tripodo C, Colombo MP. A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol 2010; 40:2902-13; PMID:20806292; http://dx.doi.org/10.1002/eji.201040505
   PubMed Web of Science ®Google Scholar
• Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 2010; 28:57-78; PMID:20307208; http://dx.doi.org/10.1146/annurev-immunol-030409-101243
   PubMed Web of Science ®Google Scholar
• Kroemer A, Xiao X, Vu MD, Gao W, Minamimura K, Chen M, Maki T, Li XC. OX40 controls functionally different T cell subsets and their resistance to depletion therapy. J Immunol 2007; 179:5584-91; PMID:17911646; http://dx.doi.org/10.4049/jimmunol.179.8.5584
   PubMed Web of Science ®Google Scholar
• Rissiek A, Baumann I, Cuapio A, Mautner A, Kolster M, Arck PC, Dodge-Khatami A, Mittrucker HW, Koch-Nolte F, Haag F et al. The expression of CD39 on regulatory T cells is genetically driven and further upregulated at sites of inflammation. J Autoimmun 2015; 58:12-20; PMID:25640206; http://dx.doi.org/10.1016/j.jaut.2014.12.007
   PubMed Web of Science ®Google Scholar
• Schuler PJ, Schilling B, Harasymczuk M, Hoffmann TK, Johnson J, Lang S, Whiteside TL. Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients. Eur J Immunol 2012; 42:1876-85; PMID:22585562; http://dx.doi.org/10.1002/eji.201142347
   PubMed Web of Science ®Google Scholar
• Friedman DJ, Kunzli BM, YI AR, Sevigny J, Berberat PO, Enjyoji K, Csizmadia E, Friess H, Robson SC. From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci U S A 2009; 106:16788-93; PMID:19805374; http://dx.doi.org/10.1073/pnas.0902869106
   PubMed Web of Science ®Google Scholar
• Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Rolinski J et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 2011; 186:4388-95; PMID:21357259; http://dx.doi.org/10.4049/jimmunol.1003251
   PubMed Web of Science ®Google Scholar
• Valmori D, Raffin C, Raimbaud I, Ayyoub M. Human RORgammat+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci U S A 2010; 107:19402-7; PMID:20962281; http://dx.doi.org/10.1073/pnas.1008247107
   PubMed Web of Science ®Google Scholar
• Bai A, Moss A, Kokkotou E, Usheva A, Sun X, Cheifetz A, Zheng Y, Longhi MS, Gao W, Wu Y et al. CD39 and CD161 modulate Th17 responses in Crohn's disease. J Immunol 2014; 193:3366-77; PMID:25172498; http://dx.doi.org/10.4049/jimmunol.1400346
   PubMed Web of Science ®Google Scholar
• Raffin C, Pignon P, Celse C, Debien E, Valmori D, Ayyoub M. Human memory Helios- FOXP3+ regulatory T cells (Tregs) encompass induced Tregs that express Aiolos and respond to IL-1beta by downregulating their suppressor functions. J Immunol 2013; 191:4619-27; PMID:24068664; http://dx.doi.org/10.4049/jimmunol.1301378
   PubMed Web of Science ®Google Scholar
• Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J et al. Mucosal Immunology. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 2015; 349:993-7; PMID:26272906; http://dx.doi.org/10.1126/science.aaa9420
   PubMed Web of Science ®Google Scholar
• Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, Seneschal J, Maurouard T, Dougall D, Davizon ES, Dumortier H et al. OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity 2015; 42:1159-70; PMID:26070486; http://dx.doi.org/10.1016/j.immuni.2015.05.012
   PubMed Web of Science ®Google Scholar
• Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011; 71:1263-71; PMID:21303976; http://dx.doi.org/10.1158/0008-5472.CAN-10-2907
   PubMed Web of Science ®Google Scholar
• Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012; 491:254-8; PMID:23034650; http://dx.doi.org/10.1038/nature11465
   PubMed Web of Science ®Google Scholar
• Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, Zhang W, Zhong Z, Sanchez-Lopez E, Wu LW et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 2014; 41:1052-63; PMID:25526314; http://dx.doi.org/10.1016/j.immuni.2014.11.009
   PubMed Web of Science ®Google Scholar
• Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013; 39:782-95; PMID:24138885; http://dx.doi.org/10.1016/j.immuni.2013.10.003
   PubMed Web of Science ®Google Scholar
• Sinicrope FA, Rego RL, Ansell SM, Knutson KL, Foster NR, Sargent DJ. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009; 137:1270-9; PMID:19577568; http://dx.doi.org/10.1053/j.gastro.2009.06.053
   PubMed Web of Science ®Google Scholar
• Sun X, Wu Y, Gao W, Enjyoji K, Csizmadia E, Muller CE, Murakami T, Robson SC. CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterol 2010; 139:1030-40; PMID:20546740; http://dx.doi.org/10.1053/j.gastro.2010.05.007
   PubMed Web of Science ®Google Scholar
• Vignali D. How many mechanisms do regulatory T cells need? Eur J Immunol 2008; 38:908-11; PMID:18395857; http://dx.doi.org/10.1002/eji.200738114
   PubMed Web of Science ®Google Scholar
• Schuler PJ, Harasymczuk M, Schilling B, Lang S, Whiteside TL. Separation of human CD4+CD39+ T cells by magnetic beads reveals two phenotypically and functionally different subsets. J Immunol Methods 2011; 369:59-68; PMID:21513715; http://dx.doi.org/10.1016/j.jim.2011.04.004
   PubMed Web of Science ®Google Scholar
• Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM. 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; PMID:20181882; http://dx.doi.org/10.4049/jimmunol.0904028
   PubMed Web of Science ®Google Scholar
• Gottschalk RA, Corse E, Allison JP. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol 2012; 188:976-80; PMID:22198953; http://dx.doi.org/10.4049/jimmunol.1102964
   PubMed Web of Science ®Google Scholar
• Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007; 5:e38; PMID:17298177; http://dx.doi.org/10.1371/journal.pbio.0050038
   PubMed Web of Science ®Google Scholar
• Kim YC, Bhairavabhotla R, Yoon J, Golding A, Thornton AM, Tran DQ, Shevach EM. Oligodeoxynucleotides stabilize Helios-expressing Foxp3+ human T regulatory cells during in vitro expansion. Blood 2012; 119:2810-8; PMID:22294730; http://dx.doi.org/10.1182/blood-2011-09-377895
   PubMed Web of Science ®Google Scholar
• Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012; 36:262-75; PMID:22326580; http://dx.doi.org/10.1016/j.immuni.2011.12.012
   PubMed Web of Science ®Google Scholar
• Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012; 37:785-99; PMID:23123060; http://dx.doi.org/10.1016/j.immuni.2012.09.010
   PubMed Web of Science ®Google Scholar
• Roychoudhuri R, Eil RL, Restifo NP. The interplay of effector and regulatory T cells in cancer. Curr Opin Immunol 2015; 33:101-11; PMID:25728990; http://dx.doi.org/10.1016/j.coi.2015.02.003
   PubMed Web of Science ®Google Scholar
• West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, Watson PH. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer 2013; 108:155-62; PMID:23169287; http://dx.doi.org/10.1038/bjc.2012.524
   PubMed Web of Science ®Google Scholar
• Chen X, Oppenheim JJ. Th17 cells and Tregs: unlikely allies. J Leukoc Biol 2014; 95:723-31; PMID:24563509; http://dx.doi.org/10.1189/jlb.1213633
   Web of Science ®Google Scholar
• Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J Immunol 2007; 178:6725-9; PMID:17513718; http://dx.doi.org/10.4049/jimmunol.178.11.6725
   PubMed Web of Science ®Google Scholar
• Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, Cerino A, Mondelli MU, Barnaba V. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119:551-64; PMID:19229109; http://dx.doi.org/10.1172/JCI36604
   PubMed Web of Science ®Google Scholar
• Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475:226-30; PMID:21753853; http://dx.doi.org/10.1038/nature10169
   PubMed Web of Science ®Google Scholar
• Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, Treuting PM, Rudensky AY. A Distinct Function of Regulatory T Cells in Tissue Protection. Cell 2015; 162:1078-89; PMID:26317471; http://dx.doi.org/10.1016/j.cell.2015.08.021
   PubMed Web of Science ®Google Scholar
• Bento DC, Jones E, Junaid S, Tull J, Williams GT, Godkin A, Ager A, Gallimore A. High endothelial venules are rare in colorectal cancers but accumulate in extra-tumoral areas with disease progression. Oncoimmunology 2015; 4:e974374; PMID:25949892; http://dx.doi.org/10.4161/2162402X.2014.974374
   PubMed Web of Science ®Google Scholar
• Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF et al. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses. Immunity 2015; 43:579-90; PMID:26341400; http://dx.doi.org/10.1016/j.immuni.2015.08.006
   PubMed Web of Science ®Google Scholar
• Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, Walker J, Gonzalez I, Meeuwsen T, Fox BA et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013; 73:7189-98; PMID:24177180; http://dx.doi.org/10.1158/0008-5472.CAN-12-4174
   PubMed Web of Science ®Google Scholar
• Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, Whiteside TL, Ferris RL. CTLA-4(+) Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis. Cancer Res 2015; 75:2200-10; PMID:25832655; http://dx.doi.org/10.1158/0008-5472.CAN-14-2788
   PubMed Web of Science ®Google Scholar
• Schuler PJ, Harasymczuk M, Schilling B, Saze Z, Strauss L, Lang S, Johnson JT, Whiteside TL. Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer. Clin Cancer Res 2013; 19:6585-96; PMID:24097865; http://dx.doi.org/10.1158/1078-0432.CCR-13-0900
   PubMed Web of Science ®Google Scholar
• Rech AJ, Mick R, Kaplan DE, Chang KM, Domchek SM, Vonderheide RH. Homeostasis of peripheral FoxP3(+) CD4 (+) regulatory T cells in patients with early and late stage breast cancer. Cancer Immunol Immunother 2010; 59:599-607; PMID:19855964; http://dx.doi.org/10.1007/s00262-009-0780-x
   PubMed Web of Science ®Google Scholar
• Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 2001; 15:445-55; PMID:11567634; http://dx.doi.org/10.1016/S1074-7613(01)00191-1
   PubMed Web of Science ®Google Scholar
• Kanai T, Watanabe M, Okazawa A, Nakamaru K, Okamoto M, Naganuma M, Ishii H, Ikeda M, Kurimoto M, Hibi T. Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease. Gastroenterol 2000; 119:1514-23; PMID:11113073; http://dx.doi.org/10.1053/gast.2000.20260
   PubMed Web of Science ®Google Scholar
• Spreafico R, Rossetti M, van den Broek T, Jansen NJ, Zhang H, Moshref M, Prakken B, van Loosdregt J, van Wijk F, Albani S. A sensitive protocol for FOXP3 epigenetic analysis in scarce human samples. Eur J Immunol 2014; 44:3141-3; PMID:25042685; http://dx.doi.org/10.1002/eji.201444627
   PubMed Web of Science ®Google Scholar