PURPOSE: Regulatory CD4(+)CD25(high)Foxp3(+) T cells (Treg) control peripheral immune tolerance. Patients with cancer, including those with hematologic malignancies, have elevated numbers of Treg in the peripheral circulation and in tumor tissues. However, mechanisms of suppression and clinical significance of Treg, especially in patients with acute myelogenous leukemia (AML), has not been well defined. EXPERIMENTAL DESIGN: We prospectively evaluated the phenotype, function, and mechanisms of suppression used by Treg in newly diagnosed untreated AML patients. The relationship between the frequency of circulating Treg and the disease status as well as treatment outcome was also evaluated. RESULTS: The percentage of circulating Treg was higher (P < 0.0001) and their phenotype was distinct in AML patients relative to normal controls. Suppression mediated by Treg coincubated with proliferating autologous responder cells was also higher (P < 0.001) in AML than that mediated by control Treg. Using Transwell inserts, we showed that interleukin-10 and transforming growth factor-beta1 production as well as cell-to-cell contact were necessary for Treg-mediated suppression. Also, the pretreatment Treg frequency predicted response to chemotherapy. Unexpectedly, patients who achieved complete remission still had elevated frequency of Treg, which mediated high levels of suppressor activity. CONCLUSIONS: Treg accumulating in the peripheral circulation of AML patients mediate vigorous suppression via contact-dependent and contact-independent mechanisms. Patients with lower Treg frequency at diagnosis have a better response to induction chemotherapy. During the post-induction period, the Treg frequency and suppressive activity remain elevated in complete remission, suggesting that Treg are resistant to conventional chemotherapy.
PURPOSE: Regulatory CD4(+)CD25(high)Foxp3(+) T cells (Treg) control peripheral immune tolerance. Patients with cancer, including those with hematologic malignancies, have elevated numbers of Treg in the peripheral circulation and in tumor tissues. However, mechanisms of suppression and clinical significance of Treg, especially in patients with acute myelogenous leukemia (AML), has not been well defined. EXPERIMENTAL DESIGN: We prospectively evaluated the phenotype, function, and mechanisms of suppression used by Treg in newly diagnosed untreated AMLpatients. The relationship between the frequency of circulating Treg and the disease status as well as treatment outcome was also evaluated. RESULTS: The percentage of circulating Treg was higher (P < 0.0001) and their phenotype was distinct in AMLpatients relative to normal controls. Suppression mediated by Treg coincubated with proliferating autologous responder cells was also higher (P < 0.001) in AML than that mediated by control Treg. Using Transwell inserts, we showed that interleukin-10 and transforming growth factor-beta1 production as well as cell-to-cell contact were necessary for Treg-mediated suppression. Also, the pretreatment Treg frequency predicted response to chemotherapy. Unexpectedly, patients who achieved complete remission still had elevated frequency of Treg, which mediated high levels of suppressor activity. CONCLUSIONS:Treg accumulating in the peripheral circulation of AMLpatients mediate vigorous suppression via contact-dependent and contact-independent mechanisms. Patients with lower Treg frequency at diagnosis have a better response to induction chemotherapy. During the post-induction period, the Treg frequency and suppressive activity remain elevated in complete remission, suggesting that Treg are resistant to conventional chemotherapy.
Authors: E Y Woo; C S Chu; T J Goletz; K Schlienger; H Yeh; G Coukos; S C Rubin; L R Kaiser; C H June Journal: Cancer Res Date: 2001-06-15 Impact factor: 12.701
Authors: Tyler J Curiel; George Coukos; Linhua Zou; Xavier Alvarez; Pui Cheng; Peter Mottram; Melina Evdemon-Hogan; Jose R Conejo-Garcia; Lin Zhang; Matthew Burow; Yun Zhu; Shuang Wei; Ilona Kryczek; Ben Daniel; Alan Gordon; Leann Myers; Andrew Lackner; Mary L Disis; Keith L Knutson; Lieping Chen; Weiping Zou Journal: Nat Med Date: 2004-08-22 Impact factor: 53.440
Authors: Megan K Levings; Romina Sangregorio; Claudia Sartirana; Anna Lisa Moschin; Manuela Battaglia; Paul C Orban; Maria-Grazia Roncarolo Journal: J Exp Med Date: 2002-11-18 Impact factor: 14.307
Authors: Giao Q Phan; James C Yang; Richard M Sherry; Patrick Hwu; Suzanne L Topalian; Douglas J Schwartzentruber; Nicholas P Restifo; Leah R Haworth; Claudia A Seipp; Linda J Freezer; Kathleen E Morton; Sharon A Mavroukakis; Paul H Duray; Seth M Steinberg; James P Allison; Thomas A Davis; Steven A Rosenberg Journal: Proc Natl Acad Sci U S A Date: 2003-06-25 Impact factor: 12.779
Authors: David A Sallman; Amy F McLemore; Amy L Aldrich; Rami S Komrokji; Kathy L McGraw; Abhishek Dhawan; Susan Geyer; Hsin-An Hou; Erika A Eksioglu; Amy Sullivan; Sarah Warren; Kyle J MacBeth; Manja Meggendorfer; Torsten Haferlach; Steffen Boettcher; Benjamin L Ebert; Najla H Al Ali; Jeffrey E Lancet; John L Cleveland; Eric Padron; Alan F List Journal: Blood Date: 2020-12-10 Impact factor: 22.113
Authors: Patrick J Schuler; Malgorzata Harasymczuk; Bastian Schilling; Zenichiro Saze; Laura Strauss; Stephan Lang; Jonas T Johnson; Theresa L Whiteside Journal: Clin Cancer Res Date: 2013-10-04 Impact factor: 12.531
Authors: Jeffrey E Rubnitz; Patrick Campbell; Yinmei Zhou; John T Sandlund; Sima Jeha; Raul C Ribeiro; Hiroto Inaba; Deepa Bhojwani; Mary V Relling; Scott C Howard; Dario Campana; Ching-Hon Pui Journal: Cancer Date: 2013-03-01 Impact factor: 6.860
Authors: Shuai Dong; Bonnie K Harrington; Eileen Y Hu; Joseph T Greene; Amy M Lehman; Minh Tran; Ronni L Wasmuth; Meixiao Long; Natarajan Muthusamy; Jennifer R Brown; Amy J Johnson; John C Byrd Journal: J Clin Invest Date: 2018-11-19 Impact factor: 14.808
Authors: Kritika Kachapati; David E Adams; Yuehong Wu; Charles A Steward; Daniel B Rainbow; Linda S Wicker; Robert S Mittler; William M Ridgway Journal: J Immunol Date: 2012-10-12 Impact factor: 5.422