{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T04:49:08Z","timestamp":1764132548506,"version":"3.37.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,1,14]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Previous studies of follicular lymphoma (FL) patients treated heterogeneously have suggested that decreased numbers of regulatory T cells correlates with improved survival. We studied advanced-stage FL patients from a single institution phase 2 trial. All patients were treated uniformly with multiagent chemotherapy and radiation. Tissue microarrays were constructed using diagnostic biopsies available in 105 patients and stained with CD4, CD8, CD25, and forkhead\/winged helix transcription factor 3 (FOXP3) antibodies. Both cell content and cell distribution were evaluated. For all antibodies, there were cases with a predominant intrafollicular or perifollicular localization of cells (follicular pattern) while others displayed a diffuse pattern. The median follow-up of living patients was 17.1 years. The International Prognostic Index score predicted overall survival (OS; P = .004) but not risk of transformation (RT). Cell content did not impact survival, while immunoarchitectural patterns of CD4\/CD8 were significant for progression-free survival (PFS; P = .056), CD25 for both PFS and OS (P = .002 and P = .024, respectively), and FOXP3+ predicted PFS, OS, and RT (P = .001, P &lt; .001 and p = .002, respectively). A Cox multivariate model showed both International Prognostic Index score and FOXP3+ pattern were independent predictors of OS (P = .008 and P &lt; .001, respectively), while only FOXP3+ pattern predicted RT (P = .004). We conclude that FOXP3+ cell distribution significantly predicts survival and RT in FL.<\/jats:p>","DOI":"10.1182\/blood-2009-07-235598","type":"journal-article","created":{"date-parts":[[2009,11,10]],"date-time":"2009-11-10T03:19:38Z","timestamp":1257823178000},"page":"289-295","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":155,"title":["The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation"],"prefix":"10.1182","volume":"115","author":[{"given":"Pedro","family":"Farinha","sequence":"first","affiliation":[{"name":"Pathology and Laboratory Medicine, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC;"},{"name":"Centro Hospitalar de Lisboa Central, Lisboa, Portugal; and"}]},{"given":"Abdulwahab","family":"Al-Tourah","sequence":"additional","affiliation":[{"name":"Medical Oncology, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC"}]},{"given":"Karamjit","family":"Gill","sequence":"additional","affiliation":[{"name":"Medical Oncology, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC"}]},{"given":"Richard","family":"Klasa","sequence":"additional","affiliation":[{"name":"Medical Oncology, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC"}]},{"given":"Joseph M.","family":"Connors","sequence":"additional","affiliation":[{"name":"Medical Oncology, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC"}]},{"given":"Randy D.","family":"Gascoyne","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, BC Cancer Agency Center for Lymphoid Cancers, Vancouver, BC;"}]}],"member":"234","reference":[{"key":"2019111801221841900_B1","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1182\/blood.V89.11.3909","article-title":"A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma.","volume":"89","author":"Anonymous","year":"1997","journal-title":"Blood"},{"issue":"23","key":"2019111801221841900_B2","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1056\/NEJM198412063112303","article-title":"The natural history of initially untreated low-grade non-Hodgkin's lymphomas.","volume":"311","author":"Horning","year":"1984","journal-title":"N Engl J Med"},{"issue":"32","key":"2019111801221841900_B3","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1200\/JCO.2008.16.0283","article-title":"Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma.","volume":"26","author":"Al-Tourah","year":"2008","journal-title":"J Clin Oncol"},{"issue":"14","key":"2019111801221841900_B4","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJM199309303291402","article-title":"A predictive model for aggressive non-Hodgkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project.","volume":"329","year":"1993","journal-title":"N Engl J Med"},{"issue":"1","key":"2019111801221841900_B5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1182\/blood-2004-06-2298","article-title":"Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment.","volume":"105","author":"Glas","year":"2005","journal-title":"Blood"},{"issue":"21","key":"2019111801221841900_B6","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1056\/NEJMoa041869","article-title":"Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.","volume":"351","author":"Dave","year":"2004","journal-title":"N Engl J Med"},{"issue":"6","key":"2019111801221841900_B7","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1182\/blood-2005-04-1565","article-title":"Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL).","volume":"106","author":"Farinha","year":"2005","journal-title":"Blood"},{"issue":"2","key":"2019111801221841900_B8","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3324\/haematol.11702","article-title":"Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma.","volume":"93","author":"Tzankov","year":"2008","journal-title":"Haematologica"},{"issue":"3","key":"2019111801221841900_B9","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1200\/JCO.2007.12.8298","article-title":"High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial.","volume":"26","author":"Canioni","year":"2008","journal-title":"J Clin Oncol"},{"issue":"12","key":"2019111801221841900_B10","first-page":"1605","article-title":"The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma.","volume":"91","author":"Alvaro","year":"2006","journal-title":"Haematologica"},{"issue":"19","key":"2019111801221841900_B11","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1158\/1078-0432.CCR-07-0778","article-title":"A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone.","volume":"13","author":"Taskinen","year":"2007","journal-title":"Clin Cancer Res"},{"issue":"4","key":"2019111801221841900_B12","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ni1178","article-title":"Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.","volume":"6","author":"Sakaguchi","year":"2005","journal-title":"Nat Immunol"},{"issue":"3","key":"2019111801221841900_B13","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1182\/blood-2005-02-0607","article-title":"CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients.","volume":"106","author":"Nishikawa","year":"2005","journal-title":"Blood"},{"issue":"6","key":"2019111801221841900_B14","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1084\/jem.194.6.823","article-title":"Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.","volume":"194","author":"Sutmuller","year":"2001","journal-title":"J Exp Med"},{"issue":"14","key":"2019111801221841900_B15","doi-asserted-by":"crossref","first-page":"8372","DOI":"10.1073\/pnas.1533209100","article-title":"Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.","volume":"100","author":"Phan","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"2019111801221841900_B16","first-page":"4766","article-title":"Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer.","volume":"61","author":"Woo","year":"2001","journal-title":"Cancer Res"},{"issue":"5","key":"2019111801221841900_B17","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.4049\/jimmunol.169.5.2756","article-title":"Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma.","volume":"169","author":"Liyanage","year":"2002","journal-title":"J Immunol"},{"issue":"5","key":"2019111801221841900_B18","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1002\/cncr.11618","article-title":"CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression.","volume":"98","author":"Sasada","year":"2003","journal-title":"Cancer"},{"issue":"2","key":"2019111801221841900_B19","first-page":"606","article-title":"Increase of regulatory T cells in the peripheral blood of cancer patients.","volume":"9","author":"Wolf","year":"2003","journal-title":"Clin Cancer Res"},{"issue":"9","key":"2019111801221841900_B20","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/nm1093","article-title":"Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.","volume":"10","author":"Curiel","year":"2004","journal-title":"Nat Med"},{"issue":"5609","key":"2019111801221841900_B21","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","article-title":"Control of regulatory T cell development by the transcription factor Foxp3.","volume":"299","author":"Hori","year":"2003","journal-title":"Science"},{"issue":"4","key":"2019111801221841900_B22","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ni909","article-title":"An essential role for Scurfin in CD4+CD25+ T regulatory cells.","volume":"4","author":"Khattri","year":"2003","journal-title":"Nat Immunol"},{"issue":"4","key":"2019111801221841900_B23","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat Immunol"},{"issue":"12","key":"2019111801221841900_B24","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1038\/sj.leu.2403965","article-title":"FOXP3, a selective marker for a subset of adult T-cell leukaemia\/lymphoma.","volume":"19","author":"Roncador","year":"2005","journal-title":"Leukemia"},{"issue":"9","key":"2019111801221841900_B25","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1182\/blood-2005-08-3376","article-title":"Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma.","volume":"107","author":"Yang","year":"2006","journal-title":"Blood"},{"issue":"20","key":"2019111801221841900_B26","doi-asserted-by":"crossref","first-page":"10145","DOI":"10.1158\/0008-5472.CAN-06-1822","article-title":"Attenuation of CD8+ T-cell function by CD4+CD25+ regulatory T cells in B-cell non-Hodgkin's lymphoma.","volume":"66","author":"Yang","year":"2006","journal-title":"Cancer Res"},{"issue":"7","key":"2019111801221841900_B27","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.4049\/jimmunol.178.7.4051","article-title":"Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3\/CD28-costimulated autologous and allogeneic CD8+CD25\u2212 and CD4+CD25\u2212 T cells.","volume":"178","author":"Hilchey","year":"2007","journal-title":"J Immunol"},{"issue":"7","key":"2019111801221841900_B28","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1182\/blood-2007-03-082578","article-title":"CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells.","volume":"110","author":"Yang","year":"2007","journal-title":"Blood"},{"issue":"11","key":"2019111801221841900_B29","doi-asserted-by":"crossref","first-page":"5359","DOI":"10.1182\/blood-2007-08-105395","article-title":"Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma.","volume":"111","author":"Mittal","year":"2008","journal-title":"Blood"},{"issue":"5","key":"2019111801221841900_B30","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.immuni.2009.04.010","article-title":"Mechanisms of foxp3+ T regulatory cell-mediated suppression.","volume":"30","author":"Shevach","year":"2009","journal-title":"Immunity"},{"issue":"9","key":"2019111801221841900_B31","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1182\/blood-2006-04-018218","article-title":"High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma.","volume":"108","author":"Carreras","year":"2006","journal-title":"Blood"},{"issue":"1","key":"2019111801221841900_B32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3324\/haematol.13574","article-title":"Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols.","volume":"94","author":"de Jong","year":"2009","journal-title":"Haematologica"},{"volume-title":"World Health Organization Classification of Tumours of Haematopoietic and lymphoid Tissues","year":"2008","author":"Swerdlow","key":"2019111801221841900_B33"},{"key":"2019111801221841900_B34","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/01621459.1958.10501452","article-title":"Nonparametric estimation for incomplete observations.","volume":"53","author":"Kaplan","year":"1958","journal-title":"Am J Stat Assoc"},{"key":"2019111801221841900_B35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","article-title":"Regression models and life tables.","volume":"34","author":"Cox","year":"1972","journal-title":"J R Stat Soc B"},{"key":"2019111801221841900_B36","first-page":"273","article-title":"\u00dcber den jetzigen Stand der Karzinomforschung.","volume":"5","author":"Ehrlich","year":"1909","journal-title":"Ned Tijdschr Geneeskd"},{"issue":"2","key":"2019111801221841900_B37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.immuni.2004.07.017","article-title":"The immunobiology of cancer immunosurveillance and immunoediting.","volume":"21","author":"Dunn","year":"2004","journal-title":"Immunity"},{"issue":"5","key":"2019111801221841900_B38","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S0092-8674(00)80856-9","article-title":"Regulatory T cells: key controllers of immunologic self-tolerance.","volume":"101","author":"Sakaguchi","year":"2000","journal-title":"Cell"},{"issue":"19","key":"2019111801221841900_B39","doi-asserted-by":"crossref","first-page":"10902","DOI":"10.1073\/pnas.1834479100","article-title":"CD4+CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses.","volume":"100","author":"Nishikawa","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"2019111801221841900_B40","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1084\/jem.20050940","article-title":"Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.","volume":"202","author":"Ko","year":"2005","journal-title":"J Exp Med"},{"issue":"2","key":"2019111801221841900_B41","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/j.1365-2249.2008.03642.x","article-title":"Depletion of CD4+ CD25+ regulatory T cells inhibits local tumour growth in a mouse model of B cell lymphoma.","volume":"152","author":"Heier","year":"2008","journal-title":"Clin Exp Immunol"},{"issue":"10","key":"2019111801221841900_B42","doi-asserted-by":"crossref","first-page":"5967","DOI":"10.4049\/jimmunol.172.10.5967","article-title":"Autoreactive T cells in healthy individuals.","volume":"172","author":"Danke","year":"2004","journal-title":"J Immunol"},{"issue":"7","key":"2019111801221841900_B43","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.4049\/jimmunol.175.7.4180","article-title":"Cutting edge: direct suppression of B cells by CD4+CD25+ regulatory T cells.","volume":"175","author":"Lim","year":"2005","journal-title":"J Immunol"},{"issue":"8","key":"2019111801221841900_B44","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1182\/blood-2008-02-138073","article-title":"Activation of natural regulatory T cells by IgG Fc-derived peptide \u201cTregitopes\u201d.","volume":"112","author":"De Groot","year":"2008","journal-title":"Blood"},{"key":"2019111801221841900_B45","first-page":"iv101","article-title":"Follicular lymphoma derived B cells are sufficient to convert CD4 T cells into CD4-CD25-FOXP3 regulatory T cells via cell-cell contact without stimulation of T cell receptor.","volume":"19","author":"Ai","year":"2008","journal-title":"Ann Oncol"},{"issue":"49","key":"2019111801221841900_B46","doi-asserted-by":"crossref","first-page":"19446","DOI":"10.1073\/pnas.0706832104","article-title":"CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes\/macrophages.","volume":"104","author":"Tiemessen","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"2019111801221841900_B47","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1182\/blood-2008-07-170274","article-title":"T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy.","volume":"113","author":"Houot","year":"2009","journal-title":"Blood"},{"key":"2019111801221841900_B48","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1200\/jco.2008.26.15_suppl.3003","article-title":"Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: preliminary results of a phase II trial of intra-tumoral CpG 7909.","volume":"26","author":"Brody","year":"2008","journal-title":"J Clin Oncol"},{"issue":"2","key":"2019111801221841900_B49","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1136\/jcp.2008.057257","article-title":"Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium).","volume":"62","author":"de Jong","year":"2009","journal-title":"J Clin Pathol"},{"issue":"1","key":"2019111801221841900_B50","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1182\/blood-2003-05-1545","article-title":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.","volume":"103","author":"Hans","year":"2004","journal-title":"Blood"},{"issue":"1","key":"2019111801221841900_B51","doi-asserted-by":"crossref","first-page":"246","DOI":"10.4049\/jimmunol.175.1.246","article-title":"Peripheral CD8+CD25+ T lymphocytes from MHC class II-deficient mice exhibit regulatory activity.","volume":"175","author":"Bienvenu","year":"2005","journal-title":"J Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/115\/2\/289\/1490419\/zh800210000289.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/115\/2\/289\/1490419\/zh800210000289.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T04:23:35Z","timestamp":1739420615000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/115\/2\/289\/26983\/The-architectural-pattern-of-FOXP3positive-T-cells"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,1,14]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2010,1,14]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2009-07-235598","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"type":"print","value":"0006-4971"},{"type":"electronic","value":"1528-0020"}],"subject":[],"published":{"date-parts":[[2010,1,14]]}}}