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Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Journal article
Authors Frida Ewald Sander
Stathis Kotsakis
Anna Rydström
Johan Aurelius
Rebecca E Riise
Charlotta Movitz
Elin Bernson
Roberta Kiffin
Anders Ståhlberg
Mats Brune
R. Foa
Kristoffer Hellstrand
Fredrik Bergh Thorén
Anna Martner
Published in Cancer Immunology Immunotherapy
Volume 66
Issue 11
Pages 1473-1484
ISSN 0340-7004
Publication year 2017
Published at Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Pathology
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 1473-1484
Language en
Links https://doi.org/10.1007/s00262-017-...
Keywords Acute myeloid leukemia, Regulatory T cells, IL-2, Immunotherapy, 1st complete remission, reactive oxygen metabolites, recombinant, interleukin-2, nk cells, histaminergic regulation, myelogenous leukemia, phase-3 trial, expression, il-2, transplantation, Oncology, Immunology
Subject categories Immunology in the medical area, Cancer and Oncology

Abstract

Regulatory T cells - (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re: Mission Trial, NCT01347996, http://www.clinicaltrials.gov) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3(+)CD25(high)CD4(+) T-regs during immunotherapy and to determine the potential impact of T-regs on relapse risk and survival. We observed a pronounced increase in T-reg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T-regs resembled thymic-derived natural T-regs (nT(regs)), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T-reg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T-reg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T-regs in later treatment cycles and a short T-reg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T-regs that may be targeted for improved anti-leukemic efficiency.

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