In the presence of AML, multiple clinical studies have demonstrated various disruptions in T cell immunity, including augmented T regulatory cells and reduced T helper cells, T cell exhaustion, and dysregulated activity of transcription factors. To begin with, T cell numbers and functions are altered to allow the progression of myeloid disease. In vitro studies show that coculture with AML cells and incubations with AML plasma inhibit the proliferation of T cells [16,17]. One proven mechanism of T cell growth inhibition is the expression of AML surface receptors that interact with T cells and alter their function. This includes leukocyte immunoglobulin-like receptor B4 (LILRB4), an inhibitory immune checkpoint receptor restrictively expressed on monocytic leukemic cells (M4 and M5 subtypes) (Figure 1). LILRB4 mediates the release of arginase-1, thus directly suppressing T cell proliferation and cytotoxicity in vitro and in vivo [18]. Another immune-suppressive molecule, CD200, is upregulated on the surface of AML cells. CD200 is a type I membrane glycoprotein belonging to the immunoglobulin superfamily whose interaction with the T cell CD200 receptor (CD200R) is associated with both increased regulatory T cell (Treg) populations and reduced memory T cell function [19] (Figure 1). This is one of several mechanisms by which the AML tumor microenvironment may alter subsets of T cells to suppress the immune response. A higher frequency of Tregs impairs the cell-mediated antileukemic immune response [20]. This is supported by an AML mouse model demonstrating an increased frequency of Tregs in vivo in addition to in vitro suppression of effector T cell function. However, with Treg depletion, in vitro effector T cell function was restored, and in vivo treatment outcomes were improved. These results suggest that the expansion of Tregs may be a mechanism of AML persistence [21]. Moreover, increased numbers of Tregs have been identified in AML patients when compared with healthy controls [20]. Shenghui et al. compared the peripheral blood (PB) and BM of 182 patients with newly diagnosed AML with those of 20 healthy age-matched controls [22]. The frequency of Treg cells in PB from patients with AML was significantly higher than that found in the disease-free counterparts (9.2% versus 5.44%, p < 0.001). Furthermore, another T cell subset, helper T cells, has demonstrated reduced numbers in AML. T helper 1 (Th1) cells predominantly secrete interferon γ (IFN-γ) and thus play a role in host defense against intracellular pathogens by promoting macrophage activation at sites of inflammation. Th1 cells exhibit a reduced frequency as well as a decreased expression of IFN-γ in AML patients compared with healthy controls (21.03% versus 11.27%, p < 0.001) [23]. Patients who obtained CR following standard induction chemotherapy exhibited a significant increase in Th1 cells as opposed to newly diagnosed patients. Additionally, increased frequencies of Th17 cells were identified in the PB and BM of AML patients when compared with healthy donors. Th17 cells secrete interleukin-17 (IL-17), which promotes the proliferation of AML cells and inhibits the differentiation of Th1 cells in vitro. Patients with higher frequencies of Th17 cells had poorer survival than those with lower numbers as well [24,25].

Figure 1. Mechanisms of T cell suppression and dysfunction induced by AML. LILRB4 is an inhibitory receptor present in monocytic AML that directly suppresses T cell proliferation. T cell proliferation and activation are also hindered due to the downregulation of transcription factors, including NFκB, by the tumor microenvironment. Upregulated expressions of checkpoint molecules, such as Tim-3, PD-1, and TIGIT, on T cells and interactions between CD200 and CD200R reduce the secretion of IFN-γ and TNF-α, thus promoting immune evasion.

Given the effective antileukemic properties of T cells, current immunotherapies aim to restore weakened T cell activity in AML patients through multiple strategies (Figure 2). In this section, we will discuss such therapeutics under clinical investigation for potential AML therapy. These include those that utilize autologous T cells and spare the use of cell modification, including tissue-infiltrating lymphocytes (TILs), bispecific antibodies, and immune checkpoint inhibitors (ICIs). We will also briefly cover the updated information of artificially engineered CAR-T cell therapy and TCR-T cell treatment. Clinical trials of these immunotherapies are summarized in Table 1.