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

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+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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-017-2040-9) contains supplementary material, which is available to authorized users.

T cell senescence and CAR-T cell exhaustion in hematological malignancies

“…Tumor-derived cAMP was shown to be responsible for the direct induction of senescence in T cells and is also a key component of the Treg cell mechanism of forcing T cells into senescence [ 48 ]. These findings correlate with re-occurring observations of Treg cell accumulations in hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and B cell lymphomas [ 49 – 52 ]. Conclusively, reduced Treg cell accumulation significantly prognosticated low relapse risk and leukemia-free survival (LFS) in AML patients [ 48 , 49 ].…”

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

“…82 It has also been described that IL-2 and histamine can mobilize the NK-and T-cell system in these patients. 139,140 However, it remains unknown whether such maintenance approach is in general efficacious and whether during this therapy minimal residual disease in AML can disappear. Moreover, patients and doctors have to be trained in detail for this therapy to avoid adverse reactions to IL-2 and/or histamine.…”

T lymphocyte subsets in cancer immunity: Friends or foes

“…have demonstrated the potential impact of Treg cells on the relapse risk in patients with AML during immunotherapy treatment . In fact, these authors have found that during the first cycle of HDC (histamine dihydrochloride)/IL‐2 treatment, which is considered as an efficient nontransplant immunotherapy for relapse prevention in AML, the number of Treg cells increased considerably in blood; highly likely because of an IL‐2 effect on Treg cells through the CD25 receptor . Furthermore, the authors have speculated that targeting immunosuppressive Treg cells could improve the efficacy of the aforesaid immune treatment .…”

“…In fact, these authors have found that during the first cycle of HDC (histamine dihydrochloride)/IL‐2 treatment, which is considered as an efficient nontransplant immunotherapy for relapse prevention in AML, the number of Treg cells increased considerably in blood; highly likely because of an IL‐2 effect on Treg cells through the CD25 receptor . Furthermore, the authors have speculated that targeting immunosuppressive Treg cells could improve the efficacy of the aforesaid immune treatment . As a matter of fact, previous studies have shown that during immune stimulation with IL‐2 in leukemia‐bearing mice, where the depletion of CD25 aimed to deplete Treg cells and limit IL‐2 effect, the survival was improved compared to the treatment alone .…”