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(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00262-017-2040-9) contains supplementary material, which is available to authorized users.