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Stem cell transplantation

Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients

Leukemia volume 35, pages 910–915 (2021)Cite this article

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for a number of high risk and/or recurrent hematological malignancies [1]. The graft-versus-tumor (GVT) effect represents the main therapeutic principle. Nowadays, tumor relapse and a systemic inflammatory reaction known as graft-versus-host disease (GVHD) still remain substantial barriers limiting allo-HSCT outcome. In fact, donor-derived alloreactive T-cells are considered key effectors of both, GVT and GVHD responses. Therefore, separating GVT from GVHD activity represents a long-sought goal.

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor regulating multiple stress-responsive pathways that protect from oxidative stress and maintain protein and metabolic homeostasis [2]. Furthermore, Nrf2 is involved in stem cell renewal [3] and chemoresistance of malignant cells [4]. Mechanistically, Nrf2 dissociates upon activation from its repressor protein Kelch-like ECH-associated protein 1 (Keap1), translocates into the nucleus, where it induces the Nrf2 target genes. Emerging evidence suggests that genetic or pharmacologic Nrf2 enhancement promotes immunological tolerance and mitigates inflammation [5, 6]. Consequently, Nrf2 has been studied in murine models of allo-HSCT yielding conflicting results. Nrf2 knock-out (−/−) donor T-cells induced less GVHD morbidity and mortality while preserving their cytotoxicity and GVT activity [7]. On the other hand, treatment with the systemic Nrf2 activator dimethyl fumarate (DMF) alleviated GVHD without affecting the GVT reaction [8]. Data from allo-HSCT patients is lacking.

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Fig. 1: Nrf2 levels in reconstituting T-cells after allo-HSCT.
Fig. 2: Impact of Nrf2 levels on T-cell exhaustion phenotype and clinical outcome.

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Acknowledgements

We are grateful to the patients, their families, and referring physicians who made this study possible. We thank Alina Kämpf (Core Unit Cell Sorting and Immunomonitoring, Erlangen) for excellent support. FK, RB, RJ, AM, and DM were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 324392634 - TRR 221.

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  1. Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany

    Franziska Karl, Andrej Stoll, Romy Böttcher-Loschinski, Martin Böttcher, Rebecca Baur, Benedikt Jacobs, Simon Völkl, Regina Jitschin, Wolf Rösler, Andreas Mackensen & Dimitrios Mougiakakos

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  1. Franziska Karl
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Contributions

FK performed research, analyzed data, and helped writing the manuscript. AS, RL, MB, BJ, and RB performed research and analyzed data. SV and WR provided patient material and clinical data. AM helped designing the study. DM designed the study, analyzed data, and wrote the manuscript.

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Correspondence to Dimitrios Mougiakakos.

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Karl, F., Stoll, A., Böttcher-Loschinski, R. et al. Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia 35, 910–915 (2021). https://doi.org/10.1038/s41375-020-0956-0

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