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Stem cell transplantation

Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity

Leukemia volume 34, pages 1885–1897 (2020)Cite this article

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Abstract

Acute graft-versus-host disease (aGVHD) and tumor relapse remain major complications after allogeneic hematopoietic stem cell transplantation. Alloreactive T cells and cancer cells share a similar metabolic phenotype to meet the bioenergetic demands necessary for cellular proliferation and effector functions. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in energy metabolism and is constantly replenished by nicotinamide phosphoribosyl-transferase (Nampt), the rate-limiting enzyme in the NAD salvage pathway. Here we show, that Nampt blockage strongly ameliorates aGVHD and limits leukemic expansion. Nampt was highly elevated in serum of patients with gastrointestinal GVHD and was particularly abundant in human and mouse intestinal T cells. Therapeutic application of the Nampt small-molecule inhibitor, Fk866, strongly attenuated experimental GVHD and caused NAD depletion in T-cell subsets, which displayed differential susceptibility to NAD shortage. Fk866 robustly inhibited expansion of alloreactive but not memory T cells and promoted FoxP3-mediated lineage stability in regulatory T cells. Furthermore, Fk866 strongly reduced the tumor burden in mouse leukemia and graft-versus-leukemia models. Ex vivo studies using lymphocytes from GVHD patients demonstrated potent antiproliferative properties of Fk866, suggesting potential clinical utility. Thus, targeting NAD immunometabolism represents a novel approach to selectively inhibit alloreactive T cells during aGVHD with additional antileukemic efficacy.

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Fig. 1: NAMPT is elevated in patients with acute GI–GVHD and is highly abundant in human and mouse intestinal T cells.
Fig. 2: Fk866-mediated Nampt inhibition mitigates acute GVHD in major mismatch models.
Fig. 3: Fk866 targets effector T cells and promotes regulatory T cells during acute GVHD.
Fig. 4: NAD depletion differentially impacts T-cell subsets.
Fig. 5: Tumor cells are highly susceptible to Fk866 in experimental leukemia and GVL models.
Fig. 6: Fk866 suppresses lymphocyte proliferation from healthy and GVHD patients and promotes iTreg.

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Acknowledgements

We thank Alexandra Pfister, Christina Schwabegger, Barbara Enrich, Heide Dierbach, Alexandra Wegmayr, and Werner Klotz for excellent technical assistance and helpful advice. We thank H.G. Knaus for generously allocating lab space and the team of the University Hospital for Radiotherapy and Radiation Oncology for providing irradiation equipment. This study was supported by the intramural funding program of the Medical University Innsbruck for young scientists MUI−START (project 2016−01−006 to RRG) and by the Austrian Society of Gastroenterology and Hepatology (ÖGGH to RRG). HT was supported by the Austrian Research Promotion Agency FFG (K−Project No. 843536) funded by the BMVIT, BMWFW, the Wirtschaftsagentur Wien and the Standortagentur Tirol.

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Author notes

  1. Romana R. Gerner

    Present address: Division of Host–Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, 92037, La Jolla, CA, USA

  2. These authors contributed equally: Romana R. Gerner, Sophie Macheiner

  3. These authors contributed equally: Herbert Tilg, David Nachbaur

Authors and Affiliations

  1. Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria

    Romana R. Gerner, Sophie Macheiner, Felix Grabherr, Lisa Mayr, Maria Effenberger, Hubert Schwaighofer, Alexander R. Moschen & Herbert Tilg

  2. Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria

    Romana R. Gerner, Sophie Macheiner, Simon Reider, Bernhard Texler & Alexander R. Moschen

  3. Department for Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria

    Kerstin Siegmund

  4. Department of Pathology, Medical University Innsbruck, Innsbruck, Austria

    Patrizia Moser

  5. Department of Internal Medicine V, Hematology & Oncology, Medical University Innsbruck, Innsbruck, Austria

    Brigitte Kircher & David Nachbaur

  6. Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria

    Herbert Oberacher

  7. Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert–Ludwigs–University, Freiburg, Germany

    Robert Zeiser

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Contributions

RRG, SM, KS, FG, LM, BT and BK performed experiments. SR and KS performed flow cytometry analysis. PM provided pathology expertise. ME, HS, ARM and DN provided access to clinical samples and HO performed LC−MS/MS studies. ARM, HT, RZ and DN provided critical feedback and contributed to paper preparation. RRG conceived the study, analyzed and interpreted data and prepared the paper together with SM and DN.

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Correspondence to Romana R. Gerner or David Nachbaur.

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Gerner, R.R., Macheiner, S., Reider, S. et al. Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity. Leukemia 34, 1885–1897 (2020). https://doi.org/10.1038/s41375-020-0709-0

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