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Stem cell transplantation

The mechanistic study behind suppression of GVHD while retaining GVL activities by myeloid-derived suppressor cells

Leukemia (2019) | Download Citation

Abstract

Graft-versus-host disease (GVHD) is a major barrier to the widespread use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating hematologic malignancies. Myeloid-derived suppressor cells (MDSCs) have been recognized as crucial immunosuppressive cells in various pathologic settings. Here, we investigated whether the unique functional properties of MDSCs could be harnessed to control allo-HSCT-associated GVHD. Using multiple murine GVHD/GVL models including both MHC-mismatched and miHA-mismatched, we demonstrated that treatment with CD115+ MDSCs efficiently suppressed GVHD but did not significantly impair graft-versus-leukemia (GVL) activity, leading to 80 and 67% protection in treated mice in GVHD and GVL models, respectively. The mechanism for this dissociation of GVHD from GVL, specifically the emergence of donor-derived NKG2D+ CD8 T cells with a memory phenotype in MDSC-treated recipient mice, was identified. NKG2D expression on donor T cells was required for eradication of allogeneic lymphoma cells. Furthermore, long-term surviving MDSC recipients that exhibited cytolytic activities against allogeneic leukemia cells had a significantly increased percentage of T regulatory cells and, more importantly, NKG2D+ CD8 T cells. These findings indicate that MDSCs can be used as a novel cell-based therapy to suppress GVHD while maintaining GVL activities through selective induction of NKG2D+ CD8 memory T cells.

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Acknowledgements

We thank Ms. Marcia Meseck for editing the manuscript. This work was supported in part by grants from NCI to S.-H. Chen (R01CA109322 and R01CA127483) and to P.-Y. Pan (R01CA140243 and R01CA188610).

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Author notes

  1. These authors contributed equally: Jilu Zhang, Hui-Ming Chen, Ge Ma

Affiliations

  1. Center for Immunotherapy Research, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA

    • Jilu Zhang
    • , Hui-Ming Chen
    • , Shu-Hsia Chen
    •  & Ping-Ying Pan
  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA

    • Ge Ma
    •  & Zuping Zhou
  3. Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, 94720, USA

    • David Raulet
  4. Research Pathology Core, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA

    • Andreana L. Rivera

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The authors declare that they have no conflict of interest.

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Correspondence to Shu-Hsia Chen or Ping-Ying Pan.

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https://doi.org/10.1038/s41375-019-0394-z