Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

Abstract

The microenviroment of acute myelogenous leukemia (AML) is suppressive for immune effector cells. Regulatory T cells (Tregs) have been recognized as a contributor factor and may be recruited and exploited by leukemic cells to evade immunesurveillance. Studies have shown that the frequencies of marrow and blood Tregs are greater in patients with AML than in control patients. Although increased Tregs have been associated with a decreased risk of GVHD after allogeneic HCT and hence may impede the graft-versus-tumor effect, recent findings indicate that that this may not be the case. Because there is a need to improve outcomes of standard treatment (chemotherapy with or without allogeneic HCT) in AML, targeting Tregs present an outstanding opportunity in AML because discoveries may apply throughout its treatment. Here, we review data on the roles of Tregs in mediating immune system-AML interactions. We focused on in vitro, animal, and observational human studies of Tregs in AML biology, development, prognosis, and therapy in different settings (eg, vaccination and HCT). Manipulation of Tregs or other types of immunomodulation may become a part of AML treatment in the future.

Figure 1

AML leukemic cells can inhibit immune effector cells by contact-dependent or -independent means. Shedding of costimulatory molecules, increased levels of suppressive cytokines, and increased IDO expression are some of the mechanisms by which leukemia cells evade from immune surveillance.

Figure 2

Some of the mechanisms by which CD25⁺CD4⁺ Tregs suppress the activation and proliferation of other T cells. The inhibition between these 2 T-cell subtypes occurs as either contact-dependent (suppressor synapse) or -independent manners. APCs play an important role in this interaction. (A) Tregs can suppress the functions of Teffs via direct contact. (B) Tregs can suppress the functions of Teffs via releasing inhibitory cytokines. (C) Tregs can complete with Teffs for the costimulatory signals of APCs. (D) Tregs can suppress APCs and thus prevent the stimulation of Teffs by APCs.

Figure 3

There are various potential ways by which the frequencies or suppressive functions of Tregs can be down-regulated. Depletion of Tregs with anti-CD25 agents has been the most common approach.