Abstract
Utilization of the adaptive immune system against malignancies, both by immune-based therapies to activate T cells in vivo to attack cancer and by T-cell therapies to transfer effector cytolytic T lymphocytes (CTL) to the cancer patient, represent major novel therapeutic advancements in oncologic therapy. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is a form of cell-based therapy, which replaces the HSC in the patient's bone marrow but also serves as a T-cell therapy due to the Graft-vs.-leukemia (GVL) effect mediated by donor T cells transferred with the graft. Allogeneic HSCT provides one potentially curative option to patients with relapsed or refractory leukemia but Graft-vs.-Host-Disease (GVHD) is the main cause of non-relapse mortality and limits the therapeutic benefit of allogeneic HSCT. Metabolism is a common cellular feature and has a key role in the differentiation and function of T cells during the immune response. Naïve T cells and memory T cells that mediate GVHD and GVL, respectively, utilize distinct metabolic programs to obtain their immunological and functional specification. Thus, metabolic targets that mediate immunosuppression might differentially affect the functional program of GVHD-mediating or GVL-mediating T cells. Components of the innate immune system that are indispensable for the activation of alloreactive T cells are also subjected to metabolism-dependent regulation. Metabolic alterations have also been implicated in the resistance to chemotherapy and survival of malignant cells such as leukemia and lymphoma, which are targeted by GVL-mediating T cells. Development of novel approaches to inhibit the activation of GVHD-specific naïve T cell but maintain the function of GVL-specific memory T cells will have a major impact on the therapeutic benefit of HSCT. Here, we will highlight the importance of metabolism on the function of GVHD-inducing and GVL-inducing alloreactive T cells as well as on antigen presenting cells (APC), which are required for presentation of host antigens. We will also analyze the metabolic alterations involved in the leukemogenesis which could differentiate leukemia initiating cells from normal HSC, providing potential therapeutic opportunities. Finally, we will discuss the immuno-metabolic effects of key drugs that might be repurposed for metabolic management of GVHD without compromising GVL.
Highlights
Quiescent immune cells use glucose, amino acids, and lipids to meet their bioenergetic demands
After allogeneic hematopoietic stem cell transplantation (HSCT), these components of the immune system function in the context of the engrafted and rapidly expanding allogeneic hematopoietic stem cell (HSC), residual leukemia cells potentially remaining at the state of Minimal residual disease (MRD) and rapidly dividing cells in host nonhematopoietic tissues that are the targets of GVHD, such as the gut [32, 33]
Our knowledge regarding the metabolic features of leukemia cells in relapsed or resistant disease in patients who undergo allogeneic HSCT is limited because relevant studies are currently missing
Summary
Quiescent immune cells use glucose, amino acids, and lipids to meet their bioenergetic demands. It has been hypothesized that leukemia cells that are resistant to treatment and responsible for relapses, have features of “LSC” that have the ability to reproduce the disease in animal models [10] These LSC, known as leukemia initiating cells, appear to have unique metabolic features that differentiate them from normal HSCs and from other leukemia cells. Protein Kinase B; ATP, Adenosine triphosphate; G-6-P, Glucose-6-phosphate; FAO, Fatty acid oxidation; HIF-1, hypoxia induced factor 1; HSCs, hematopoietic stem cells; Mcl-1, myeloid cell leukemia 1; mTOR, Mechanistic/mammalian target of rapamycin; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; TCA, Tricarboxylic acid cycle. After allogeneic HSCT, these components of the immune system function in the context of the engrafted and rapidly expanding allogeneic HSC, residual leukemia cells potentially remaining at the state of MRD and rapidly dividing cells in host nonhematopoietic tissues that are the targets of GVHD, such as the gut [32, 33]. We will provide rationale for potential therapeutic interventions by targeting metabolic pathways that guide the differentiation and function of these immune cells in the context of alloHSCT
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