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

Cancer Immunol Immunother. 2017 Nov;66(11):1473-1484. doi: 10.1007/s00262-017-2040-9. Epub 2017 Jul 18.


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, ) 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+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), 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 Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg 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 Tregs that may be targeted for improved anti-leukemic efficiency.

Keywords: Acute myeloid leukemia; IL-2; Immunotherapy; Regulatory T cells.

Publication types

  • Clinical Trial, Phase IV

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Female
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Histamine / immunology
  • Histamine / therapeutic use
  • Humans
  • Immunotherapy / methods*
  • Interleukin-2 / immunology
  • Interleukin-2 / therapeutic use
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Leukemia, Myeloid / immunology*
  • Leukemia, Myeloid / pathology
  • Leukemia, Myeloid / therapy*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Recurrence, Local
  • Outcome Assessment, Health Care / methods
  • Outcome Assessment, Health Care / statistics & numerical data
  • Prognosis
  • Proportional Hazards Models
  • Remission Induction
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Telomere / genetics
  • Young Adult


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Histamine

Associated data