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

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^highCD4⁺ 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.