2,665
Views
22
CrossRef citations to date
0
Altmetric
Original Research

Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Article: e1387705 | Received 05 Apr 2017, Accepted 29 Sep 2017, Published online: 09 Nov 2017

References

  • Liu C, Workman CJ, Vignali DA. Targeting regulatory T cells in tumors. FEBS J. 2016;238:2731–48.
  • Whiteside TL. Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert opinion on biological therapy. 2014;14:1411–25.
  • Adeegbe DO, Nishikawa H. Natural and induced T regulatory cells in cancer. Front Immunol. 2013;4:190.
  • Burocchi A, Colombo MP, Piconese S. Convergences and divergences of thymus- and peripherally derived regulatory T cells in cancer. Front Immunol. 2013;4:247.
  • Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306. doi:10.1038/nrc3245. PMID:22419253
  • Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443–6. doi:10.1038/74704. PMID:10742152
  • Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, Brogdon JL. Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210:1685–93. doi:10.1084/jem.20130573. PMID:23897982
  • Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, Shimizu J, Nomura T, Chiba T, Sakaguchi S. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med. 2005;202:885–91. doi:10.1084/jem.20050940. PMID:16186187
  • Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695–710. doi:10.1084/jem.20130579. PMID:23897981
  • Bulliard Y, Jolicoeur R, Zhang J, Dranoff G, Wilson NS, Brogdon JL. OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol Cell Biol. 2014;92:475–80. doi:10.1038/icb.2014.26. PMID:24732076
  • Petrillo MG, Ronchetti S, Ricci E, Alunno A, Gerli R, Nocentini G, Riccardi C. GITR+ regulatory T cells in the treatment of autoimmune diseases. Autoimmun Rev. 2015;14:117–26. doi:10.1016/j.autrev.2014.10.011. PMID:25449679
  • Seo N, Hayakawa S, Takigawa M, Tokura Y. Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology. 2001;103:449–57. doi:10.1046/j.1365-2567.2001.01279.x. PMID:11529935
  • Morikawa H, Sakaguchi S. Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol Rev. 2014;259:192–205. doi:10.1111/imr.12174. PMID:24712467
  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. 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. doi:10.1084/jem.20030152. PMID:14676299
  • Bianchini R, Bistoni O, Alunno A, Petrillo MG, Ronchetti S, Sportoletti P, Bocci EB, Nocentini G, Gerli R, Riccardi C. CD4(+) CD25(low) GITR(+) cells: a novel human CD4(+) T-cell population with regulatory activity. Eur J Immunol. 2011;41:2269–78. doi:10.1002/eji.201040943. PMID:21557210
  • Nocentini G, Cari L, Migliorati G, Riccardi C. The role of GITR single-positive cells in immune homeostasis. Immun Inflamm Dis. 2017;5:4–6. doi:10.1002/iid3.148. PMID:28250919
  • Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19:739–46. doi:10.1038/nm.3179. PMID:23624599
  • Roncarolo MG, Gregori S, Bacchetta R, Battaglia M. Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol. 2014;380:39–68. PMID:25004813
  • Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011;11:119–30. doi:10.1038/nri2916. PMID:21267013
  • Rezende RM, da Cunha AP, Kuhn C, Rubino S, M'Hamdi H, Gabriely G, Vandeventer T, Liu S, Cialic R, Pinheiro-Rosa N, et al. Identification and characterization of latency-associated peptide-expressing gammadelta T cells. Nat Commun. 2015;6:8726. doi:10.1038/ncomms9726. PMID:26644347
  • Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259:88–102. doi:10.1111/imr.12160. PMID:24712461
  • Feuerer M, Hill JA, Mathis D, Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009;10:689–95. doi:10.1038/ni.1760. PMID:19536194
  • Padovani CT, Bonin CM, Tozetti IA, Ferreira AM, Fernandes CE, Costa IP. Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection. Rev Soc Bras Med Trop. 2013;46:288–92. doi:10.1590/0037-8682-0029-2013. PMID:23856878
  • Sacchetti C, Rapini N, Magrini A, Cirelli E, Bellucci S, Mattei M, Rosato N, Bottini N, Bottini M. In vivo targeting of intratumor regulatory T cells using PEG-modified single-walled carbon nanotubes. Bioconjug Chem. 2013;24:852–8. doi:10.1021/bc400070q. PMID:23682992
  • Ronchetti S, Ricci E, Petrillo MG, Cari L, Migliorati G, Nocentini G, Riccardi C. Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells. J Immunol Res. 2015;2015:171520. doi:10.1155/2015/171520. PMID:25961057
  • Torrey H, Butterworth J, Mera T, Okubo Y, Wang L, Baum D, Defusco A, Plager S, Warden S, Huang D, et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci Signal. 2017;10. doi:10.1126/scisignal.aaf8608. PMID:28096513
  • Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ. Anti-CTLA-4 antibodies of IgG2 a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32–42. doi:10.1158/2326-6066.CIR-13-0013. PMID:24777248
  • Gabriely G, da Cunha AP, Rezende RM, Kenyon B, Madi A, Vandeventer T, Skillin N, Rubino S, Garo L, Mazzola MA, et al. Targeting latency-associated peptide promotes antitumor immunity. Science Immunology. 2017;2. doi:10.1126/sciimmunol.aaj1738. PMID:28763794
  • De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJ, Provasi E, Sarnicola ML, Panzeri I, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity. 2016;45:1135–47. doi:10.1016/j.immuni.2016.10.021. PMID:27851914
  • Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM, Rudensky AY. Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity. 2016;45:1122–34. doi:10.1016/j.immuni.2016.10.032. PMID:27851913
  • 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. doi:10.1016/j.immuni.2013.10.003. PMID:24138885
  • Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61. doi:10.1016/j.cell.2014.12.033. PMID:25594174
  • Şenbabaoğlu Y, Winer AG, Gejman RS, Liu M, Luna A, Ostrovnaya I, Weinhold N, Lee W, Kaffenberger SD, Chen YB, et al. The landscape of T cell infiltration in human cancer and its association with antigen presenting gene expression. bioRxiv. 2015.
  • Hruz T, Laule O, Szabo G, Wessendorp F, Bleuler S, Oertle L, Widmayer P, Gruissem W, Zimmermann P. Genevestigator v3: a reference expression database for the meta-analysis of transcriptomes. Adv Bioinformatics. 2008;2008:420747. doi:10.1155/2008/420747. PMID:19956698
  • Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, Ganly I, Hakimi AA, Chan TA, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1:e89829. doi:10.1172/jci.insight.89829. PMID:27777979
  • Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, Hackl H, Trajanoski Z. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18:248–62. doi:10.1016/j.celrep.2016.12.019. PMID:28052254
  • Barrett T, Suzek TO, Troup DB, Wilhite SE, Ngau WC, Ledoux P, Rudnev D, Lash AE, Fujibuchi W, Edgar R. NCBI GEO: mining millions of expression profiles-database and tools. Nucleic Acids Res. 2005;33:D562–6. doi:10.1093/nar/gki022. PMID:15608262
  • Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang YA, Williams E, Dylag M, Kurbatova N, Brandizi M, Burdett T, et al. ArrayExpress update-simplifying data submissions. Nucleic Acids Res. 2015;43:D1113–6. doi:10.1093/nar/gku1057. PMID:25361974
  • Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, Selves J, Laurent-Puig P, Sautes-Fridman C, Fridman WH, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17:218. doi:10.1186/s13059-016-1070-5. PMID:27765066
  • Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71. doi:10.1146/annurev-immunol-031210-101324. PMID:21219185
  • Diederichsen AC, Hjelmborg J, Christensen PB, Zeuthen J, Fenger C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother. 2003;52:423–8. doi:10.1007/s00262-003-0388-5. PMID:12695859
  • Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74. doi:10.1172/JCI31202. PMID:17476346
  • Clancy T, Hovig E. Profiling networks of distinct immune-cells in tumors. BMC Bioinformatics. 2016;17:263. doi:10.1186/s12859-016-1141-3. PMID:27377892
  • Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH. 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;61:4766–72. PMID:11406550
  • Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61. doi:10.4049/jimmunol.169.5.2756. PMID:12193750
  • Massague J. TGFbeta in Cancer. Cell. 2008;134:215–30. doi:10.1016/j.cell.2008.07.001. PMID:18662538
  • Alshaker HA, Matalka KZ. IFN-gamma, IL-17 and TGF-beta involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors. Cancer Cell Int. 2011;11:33. doi:10.1186/1475-2867-11-33. PMID:21943203
  • Aruga A, Aruga E, Tanigawa K, Bishop DK, Sondak VK, Chang AE. Type 1 versus type 2 cytokine release by Vbeta T cell subpopulations determines in vivo antitumor reactivity: IL-10 mediates a suppressive role. J Immunol. 1997;159:664–73. PMID:9218581
  • Wu C, Thalhamer T, Franca RF, Xiao S, Wang C, Hotta C, Zhu C, Hirashima M, Anderson AC, Kuchroo VK. Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity. 2014;41:270–82. doi:10.1016/j.immuni.2014.06.011. PMID:25065622
  • Rifkin DB. Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem. 2005;280:7409–12. doi:10.1074/jbc.R400029200. PMID:15611103
  • Bu M, Shen Y, Seeger WL, An S, Qi R, Sanderson JA, Cai Y. Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8(+) T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biol. 2016;37:3949–56. doi:10.1007/s13277-015-4237-x. PMID:26482613
  • Madireddi S, Eun SY, Lee SW, Nemcovicova I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M. Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. J Exp Med. 2014;211:1433–48. doi:10.1084/jem.20132687. PMID:24958847
  • Kang CW, Dutta A, Chang LY, Mahalingam J, Lin YC, Chiang JM, Hsu CY, Huang CT, Su WT, Chu YY, et al. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci Rep. 2015;5:15659. doi:10.1038/srep15659. PMID:26493689
  • Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009;106:13445–50. doi:10.1073/pnas.0901944106. PMID:19651619
  • Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer. 2016;67:1–10. doi:10.1016/j.ejca.2016.06.028. PMID:27591414
  • Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013;123:2447–63. doi:10.1172/JCI64859. PMID:23728179
  • Nocentini G, Cari L, Ronchetti S, Riccardi C. Modulation of tumor immunity: a patent evaluation of WO2015026684A1. Expert Opin Ther Pat. 2016;26:417–25. doi:10.1517/13543776.2016.1118061. PMID:26560753
  • Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:e10436. doi:10.1371/journal.pone.0010436. PMID:20454651
  • Nocentini G, Cari L, Riccardi C. GITR: A Modulator of Regulatory and Effector T-cell Activity, Crucial in Tumour Rejection and Autoimmune Diseses. eLS. Chichester: John Wiley & Sons Ltd, 2017. doi:10.1002/9780470015902.a0026242.
  • Kim YH, Shin SM, Choi BK, Oh HS, Kim CH, Lee SJ, Kim KH, Lee DG, Park SH, Kwon BS. Authentic GITR signaling fails to induce tumor regression unless Foxp3+ Regulatory T cells are depleted. J Immunol. 2015;195:4721–9. doi:10.4049/jimmunol.1403076. PMID:26423152
  • Miska J, Rashidi A, Chang AL, Muroski ME, Han Y, Zhang L, Lesniak MS. Anti-GITR therapy promotes immunity against malignant glioma in a murine model. Cancer Immunol Immunother. 2016;65:1555–67. doi:10.1007/s00262-016-1912-8. PMID:27734112
  • Leyland R, Watkins A, Mulgrew K, Holoweckyj N, Bamber L, Tigue NJ, Offer E, Andrews J, Yan L, Mullins S, et al. A novel murine GITR ligand fusion protein induces antitumor activity as a monotherapy, which is further enhanced in combination with an OX40 agonist. Clin Cancer Res. 2017;23(13):3416–3427. doi:10.1158/1078-0432.CCR-16-2000. PMID:28069723
  • Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, Sharpe AH, Kuchroo VK. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186:1338–42. doi:10.4049/jimmunol.1003081. PMID:21199897
  • Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569–81. doi:10.1016/j.immuni.2014.02.012. PMID:24745333
  • Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, Smyth MJ, Kuchroo VK, Anderson AC. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015;125:4053–62. doi:10.1172/JCI81187. PMID:26413872
  • Fuhrman CA, Yeh WI, Seay HR, Saikumar Lakshmi P, Chopra G, Zhang L, Perry DJ, McClymont SA, Yadav M, Lopez MC, et al. Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol. 2015;195:145–55. doi:10.4049/jimmunol.1402381. PMID:25994968
  • Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL. 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. doi:10.4049/jimmunol.180.11.7327. PMID:18490732
  • Scurr M, Ladell K, Besneux M, Christian A, Hockey T, Smart K, Bridgeman H, Hargest R, Phillips S, Davies M, et al. Highly prevalent colorectal cancer-infiltrating LAP(+) Foxp3(-) T cells exhibit more potent immunosuppressive activity than Foxp3(+) regulatory T cells. Mucosal Immunol. 2014;7:428–39. doi:10.1038/mi.2013.62. PMID:24064667
  • Abd Al Samid M, Chaudhary B, Khaled YS, Ammori BJ, Elkord E. Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients. Oncotarget. 2016;7:14083–94. doi:10.18632/oncotarget.7334. PMID:26885615
  • 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. doi:10.1002/eji.201142347. PMID:22585562
  • Whiteside TL. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother. 2014;63:67–72. doi:10.1007/s00262-013-1490-y. PMID:24213679
  • Collin M. Immune checkpoint inhibitors: a patent review (2010-2015). Expert Opin Ther Pat. 2016;26:555–64. doi:10.1080/13543776.2016.1176150. PMID:27054314
  • Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, Schenkel JM, Boomer JS, Green JM, Yagita H, et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol. 2014;15:473–81. doi:10.1038/ni.2849. PMID:24633226
  • Govindaraj C, Scalzo-Inguanti K, Madondo M, Hallo J, Flanagan K, Quinn M, Plebanski M. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin Immunol. 2013;149:97–110. doi:10.1016/j.clim.2013.07.003. PMID:23948613
  • Bonnefoy N, Bastid J, Alberici G, Bensussan A, Eliaou JF. CD39: A complementary target to immune checkpoints to counteract tumor-mediated immunosuppression. Oncoimmunology. 2015;4:e1003015. doi:10.1080/2162402X.2014.1003015. PMID:26155397
  • Al-Lamki RS, Sadler TJ, Wang J, Reid MJ, Warren AY, Movassagh M, Lu W, Mills IG, Neal DE, Burge J, et al. Tumor necrosis factor receptor expression and signaling in renal cell carcinoma. Am J Pathol. 2010;177:943–54. doi:10.2353/ajpath.2010.091218. PMID:20566746
  • Plitas G, Rudensky AY. Regulatory T Cells: Differentiation and Function. Cancer Immunol Res. 2016;4:721–5. doi:10.1158/2326-6066.CIR-16-0193. PMID:27590281
  • Robins HS, Ericson NG, Guenthoer J, O'Briant KC, Tewari M, Drescher CW, Bielas JH. Digital genomic quantification of tumor-infiltrating lymphocytes. Sci Transl Med. 2013;5:214ra169. doi:10.1126/scitranslmed.3007247. PMID:24307693
  • Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5:R80. doi:10.1186/gb-2004-5-10-r80. PMID:15461798

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.