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

• Published in: Cancer Immunology Immunotherapy 2017-11, Vol.66 (11), p.1473-1484
• Main Authors: Sander, Frida Ewald, Nilsson, Malin, Rydström, Anna, Aurelius, Johan, Riise, Rebecca E., Movitz, Charlotta, Bernson, Elin, Kiffin, Roberta, Ståhlberg, Anders, Brune, Mats, Foà, Robin, Hellstrand, Kristoffer, Thorén, Fredrik B., Martner, Anna
• Format: Article
• Language: English
• Subjects: 1st complete remission; Acute Disease; Acute myeloid leukemia; Adolescent; Adult; Aged; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer Research; CD25 antigen; Cell cycle; Cell proliferation; Consolidation; CTLA-4 protein; expression; Female; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Foxp3 protein; Histamine; Histamine - immunology; Histamine - therapeutic use; histaminergic regulation; Humans; IL-2; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Immunoregulation; Immunosuppression; Immunotherapy; Immunotherapy - methods; Interleukin 2; Interleukin-2 - immunology; Interleukin-2 - therapeutic use; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Leukemia; Leukemia, Myeloid - immunology; Leukemia, Myeloid - pathology; Leukemia, Myeloid - therapy; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine & Public Health; Middle Aged; Multivariate Analysis; myelogenous leukemia; Myeloid leukemia; Neoplasm Recurrence, Local; nk cells; Oncology; Original; Original Article; Outcome Assessment (Health Care) - methods; Outcome Assessment (Health Care) - statistics & numerical data; Peripheral blood; phase-3 trial; Prognosis; Proportional Hazards Models; reactive oxygen metabolites; recombinant; Regulatory T cells; Remission; Remission Induction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Telomere - genetics; Thymus; transplantation; Young Adult
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-017-2040-9

Regulatory T cells (T regs ) 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.