Present and Future Role of Immune Targets in Acute Myeloid Leukemia

Abstract

It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs.

Keywords: acute myeloid leukemia; drug resistance; immune escape; immune therapy.

Figure 1

Schematic representation of the cellular mechanisms of anti-tumor surveillance escape in AML. (A) Cellular cross-talks: leukemic stem cells (LSCs) and T cells direct interaction, through major histocompatibility complex (MHC) and over-expressed immune checkpoint ligands (PD-L1), causes functional defects in anti-tumor immunity. LSCs induce the expansion of immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and leukemia-associated macrophages (LAMs). (B) Surface receptors: LSCs can hamper both T- and NK-cell effector functions by aberrantly overexpressing inhibitory ligands such as CD155, CD80, PD-L1, and galectin-9 (Gal-9). (C) Genetic regulation: the activation of immune checkpoint pathways, such as PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and the expression of CD44, a cell-adhesion molecule that has been shown to be involved in the promotion of resistance to drug-induced apoptosis, prevent the appropriate anti-tumor immunity. Moreover, epigenetic mechanisms may result in the downregulation of MHC expression in AML cells, leading to immune escape and relapse in AML. (D) Secreted products: LSCs release inhibitory mediators, either as soluble molecules or as a component of exosomes; furthermore, induced immune cell (Tregs, CD8+ T cells) anergy lowers the levels of inhibitory cytokines. Among these factors that alter the bone marrow microenvironment milieu, a relevant role is played by indoleamine 2,3-dioxygenase (IDO), interferon-gamma (IFN-γ), transforming growth factor beta (TGF-β), arginase 1 (Arg 1), and interleukin 10 and 15 (IL-10 and IL-15). Figure created in Biorender.com.

Figure 2

Major mechanisms of the maintenance of immune tolerance and potential therapeutic targets. Given the pivotal role of LSC-induced immune escape in the development and relapse of AML, an important treatment strategy to restore the function of anti-tumor immune cells is the blockade of immune checkpoints by monoclonal antibodies. Among the most promising targets are CD47, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD200, the PD1/PD-L1 axis, and T-cell immunoglobulin and mucin domain-containing protein (Tim-3). Figure created in Biorender.com.