Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia.
OBJECTIVE
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.


METHODS
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.
Szczepanski
Miroslaw J
MJ
Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Szajnik
Marta
M
Czystowska
Malgorzata
M
Mandapathil
Magis
M
Strauss
Laura
L
Welsh
Ann
A
Foon
Kenneth A
KA
Whiteside
Theresa L
TL
Boyiadzis
Michael
M
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007951:Leukemia, Myeloid / Q000097:blood / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D015704:CD4 Antigens; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D000255:Adenosine Triphosphate