Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans

Uhl, Franziska Maria; Chen, Sophia; O’Sullivan, David; Edwards-Hicks, Joy; Richter, Gesa; Haring, Eileen; Andrieux, Geoffroy; Halbach, Sebastian; Apostolova, Petya; Büscher, Jörg; Duquesne, Sandra; Melchinger, Wolfgang; Sauer, Barbara; Shoumariyeh, Khalid; Schmitt‐Graeff, Annette; Kreutz, Marina; Lübbert, Michael; Duyster, Justus; Brummer, Tilman; Boerries, Melanie; Madl, Tobias; Blazar, Bruce R.; Groß, Olaf; Pearce, Erika L.; Zeiser, Robert

doi:10.1126/scitranslmed.abb8969

Cited by 83 publications

(75 citation statements)

References 42 publications

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“…Recent findings in immune cell metabolic reprogramming indicated the possibilities of clinical metabolic interventions for cancer treatment ( 12 , 146 ). Metabolic intervention by sodium bicarbonate helps neutralize the lactate acidity in AML, leading to improved efficacy of CD8+T cell immunotherapy ( 147 ). Pearce group showed that transient glucose restriction (TGR) in CD8+effector T cell before adoptive transfer metabolically condition effector T cell functions and enhance tumor clearance in mice ( 148 ).…”

Section: A New Frontier Of Conditioning Metabolism To Enhance Immune Effector Cell Functions In Immunotherapiesmentioning

confidence: 99%

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021

Front. Immunol.

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Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

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Section: A New Frontier Of Conditioning Metabolism To Enhance Immune Effector Cell Functions In Immunotherapiesmentioning

confidence: 99%

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021

Front. Immunol.

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“… 43 The importance of the glycolytic activity of T-cells to enhance GvL immunity was recently demonstrated. 47 T-cells from patients relapsing after allo-HCT showed reduced glycolysis that was mechanistically linked to increased lactic acid secreted by leukemia cells leading to a reduction of the intracellular pH in T-cells. Metabolic reprogramming of donor T-cells enhanced GvL activity and prolonged the survival of leukemia-bearing mice.…”

Section: Metabolic Reprogramming Of T-cellsmentioning

confidence: 99%

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Braun

Zeiser

2021

HemaSphere

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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versushost disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and lowdose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.

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“…Multiple approaches are under investigation to improve the after-transplantation overall survival [ 109 ] in elderly patients. They range from the combinations with different chemotherapies [ 110 ] and radiotherapies to enhance T cells’ metabolic activity restoring the GVL [ 111 ].…”

Section: Adoptive Cell Transfermentioning

confidence: 99%

Acute Myeloid Leukemia: Is It T Time?

Khoud

Ingegnere

Quesnel

et al. 2021

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous disease driven by impaired differentiation of hematopoietic primitive cells toward myeloid lineages (monocytes, granulocytes, red blood cells, platelets), leading to expansion and accumulation of “stem” and/or “progenitor”-like or differentiated leukemic cells in the bone marrow and blood. AML progression alters the bone marrow microenvironment and inhibits hematopoiesis’ proper functioning, causing sustained cytopenia and immunodeficiency. This review describes how the AML microenvironment influences lymphoid lineages, particularly T lymphocytes that originate from the thymus and orchestrate adaptive immune response. We focus on the elderly population, which is mainly affected by this pathology. We discuss how a permissive AML microenvironment can alter and even worsen the thymic function, T cells’ peripheral homeostasis, phenotype, and functions. Based on the recent findings on the mechanisms supporting that AML induces quantitative and qualitative changes in T cells, we suggest and summarize current immunotherapeutic strategies and challenges to overcome these anomalies to improve the anti-leukemic immune response and the clinical outcome of patients.

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Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans

Cited by 83 publications

References 42 publications

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Acute Myeloid Leukemia: Is It T Time?

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