The Induction of a Permissive Environment to Promote T Cell Immune Evasion in Acute Myeloid Leukemia: The Metabolic Perspective

Abstract

Acute myeloid leukemia (AML) is the acute leukemia with highest incidence amongst adults. Despite significant improvements in understanding the genomic landscape and the introduction of novel drugs, long-term outcome remains unsatisfactory. Recently, immunotherapeutic approaches have heralded a new era in cancer treatment. The success of allogeneic hematopoietic stem cell transplantation in AML highlights the disease's immunoresponsiveness. Several immunotherapeutic applications are currently under clinical evaluation and include immune checkpoint blockades, T cell-engaging antibodies, and genetically engineered T cells. However, immunoevasive mechanisms employed by AML blasts severely hamper our endeavors. A better understanding of the underlying mechanisms remains a prerequisite for improving treatment efficacy. One of the hallmarks of the cancer cells is metabolic reprogramming, introduced by Otto Warburg's seminal studies during the beginnings of the last century. Nowadays, it is well established that metabolic adaptation is not just an epiphenomenon during oncogenesis but rather a necessity for tumor development and progression. Furthermore, accumulating data suggest an important role of aberrant tumor cell metabolism for immune escape. AML blasts display a number of metabolic alterations that could be linked to immunoregulation, and these include competition over substrates, abundant release of bioactive metabolites, and an overall microenvironmental metabolic re-modeling that favors the induction or survival of immunoregulatory cell subsets such as regulatory T cells. In this review, we outline the immunoevasive character of the AML blasts' bioenergetics, set it into context with oncogenic mutations, and discuss potentially suitable countermeasures and their limitations.

Keywords: AML—acute myeloid leukemia; immunoescape mechanisms; immunotherapy; microenvironment; tumor metabolism.

Figure 1

Metabolic alterations in AML blasts. This schematic overview summarizes the bioenergetic rewiring in AML blasts. The black cycles represent key metabolic enzymes. Identified genetic aberrations and/or microenvironmental components that promote (+, green) or suppress (-, red) metabolic pathways in AML blasts are numbered 1–5 and can be found in the upper right box. Affected pathways, metabolic products, or enzymes are labeled with the according number. glu, glucose; gln, glutamine; glu-6-P, glucose-6-phosphate; fru-6-P, fructose-6-phosphate; α-KG, α-ketoglutarate; 2-HG, 2-hydroxyglutarate; ROS, reactive oxygen species; HK2, hexokinase 2; PFK, phosphofructokinase; G6PD, glucose-6-phosphate dehydrogenase; PK, pyruvate kinase; LDHA, lactate dehydrogenase A; PDH, pyruvate dehydrogenase; CS, citrate synthase; IDH, isocitrate dehydrogenase; GLS, glutaminase; mTOR, mammalian target of rapamycin; PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation.

Figure 2

Enhanced tryptophan-turnover in AML blasts. Increased expression of indoleamine-2,3 dioxygenase 1 (IDO1) in AML blasts leads to tryptophan (Trp) depletion. It is catabolized to kynurenine (Kyn), resulting in extracellular kyn accumulation. A proportion of kyn is intracellularly converted to kynurenic acid (Kyna) by kyn aminotransferase (Kat) or to 3-hydroxy kyn (3-HK) by kyn 3-monooxygenase (Kmo). Subsequently, 3-HK is further processed into 3-hydroxanthranilic acid (3-HAA) by KYNase, which is further converted into quinolinic acid (QA) and picolinic acid (PA). The microenvironmental shortage of Trp and simultaneous abundance of Kyn promote activation of the aryl-hydrocarbon receptor (AhR) and the non-derepressing 2 protein kinase (GCN2) and suppress the mammalian target of the rapamycin (mTOR) pathway, thus skewing immune responses away from immunoreactivity (by impeding conventional T cells) toward immunotolerance (by reinforcing regulatory T cells/T_Regs).

Figure 3

Immunometabolic interplay in AML. Increased glycolytic activity, expression of arginase II (Arg II) and indoleamine-2,3-dioxygenase 1 (IDO1) in AML blasts lead to glucose, tryptophan, and arginine depletion; these are required for proper T cell functionality (= competition). Stromal cells are capable of further triggering those metabolic pathways. Aerobic glycolysis, NADPH-oxidase 2 (NOX2) activity, and IDO1 in AML blasts abundantly produce bioactive metabolites (= waste products) such as lactate, reactive oxygen species (ROS), and kynurenine that hamper T cell responses. Increased levels of lactate, ROS, and kynurenine lead to a preferential survival and/or induction of regulatory T cells (T_Regs) and the induction of myeloid derived suppressor cells (MDSCs) (= tolerogenic cells). The PD-L1 expression of AML blasts (= immune checkpoint) could cause a state of immunometabolic anergy in T cells by binding its cognate receptor PD-1.