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Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras

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Abstract

Allogeneic hematopoietic stem cell transplantation is an emerging treatment option for solid tumors because of its capacity to elicit immune graft-versus-tumor effects. However, these are often limited and associated with GvHD. Adoptive recipient leukocyte infusion (RLI) was shown to enhance anti-tumor responses of allogeneic bone marrow transplantation in murine neuroblastoma (Neuro2A)-bearing chimeras. In contrast to the clinically used donor leukocyte infusion, the RLI anti-tumor effect—elicited by host-versus-graft lymphohematopoietic reactivity—does not cause GvHD; however, the tumor growth-inhibitory effect is incomplete, because overall survival is not prolonged. Here, we studied the anti-solid tumor mechanisms of RLI with the objective to improve its efficacy. Host-versus-graft reactivity following RLI was associated with a systemic cytokine storm, lymph node DC activation, and systemic expansion of host-derived IFN-γ-expressing CD4+ T cells and IFN-γ-and granzyme B-expressing CD8+ T cells, which acquired killing activity against Neuro2A and third-party tumor cells. The tumor showed up-regulation of MHC class I and a transient accumulation of IFN-γ-and granzyme B-expressing CD8+ T cells: the intra-tumor decline in cytotoxic CD8+ T cells coincided with a systemic—and to a lesser extent intra-tumoral—expansion of MDSC. In vivo MDSC depletion with 5-FU significantly improved the local tumor growth-inhibitory effect of RLI as well as overall survival. In conclusion, the RLI-induced alloreactivity gives rise to a host-derived cytotoxic T-cell anti-neuroblastoma response, but also drives an expansion of host-type MDSC that counteracts the anti-tumor effect. This finding identifies MDSC as a novel target to increase the effectiveness of RLI, and possibly other cancer immunotherapies.

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Abbreviations

AlloBMT:

Allogeneic bone marrow transplantation

AlloHSCT:

Allogeneic hematopoietic stem cell transplantation

APC:

Allophycocyanin

CBA:

Cytometric bead array

CCL2:

Chemokine (C-C motif) ligand 2

DLI:

Donor leukocyte infusion

FasL:

Fas ligand

GvHD:

Graft-versus-host disease

GvT:

Graft-versus-tumor

iNKT:

Invariant natural killer T cells

M-/G-MDSC:

Monocytic/granulocytic myeloid-derived suppressor cells

MHC-I:

MHC class I

MHC-II:

MHC class II

NO:

Nitric oxide

NOD/SCID:

Nonobese diabetic/severe combined immunodeficiency

RLI:

Recipient leukocyte infusion

Th1:

T helper 1 cells

Treg:

T regulatory cells

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Acknowledgements

The authors gratefully acknowledge the Olivia Hendrickx Research Fund (http://www.olivia.be) and the Fund for Scientific Research (FWO) Flanders (http://www.FWO.be) for supporting this work with research grants, and the Olivia Hendrickx Research Fund for supporting Isabelle Dierckx de Casterlé with a fellowship grant. The authors thank Stefaan W. Van Gool for the scientific advice on the tumor model, and Louis Boon for providing the anti-PD-1 (clone RMP1-14) mAb.

Funding

This work was supported by the Olivia Hendrickx Research Fund (http://www.olivia.be) and by the FWO Grants G054010N (of A. D. Billiau) and 12V9218N (of F. Poosti).

Author information

Authors and Affiliations

  1. Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, Katholieke Universiteit (KU) Leuven, Herestraat 49, Box 811, 3000, Leuven, Belgium

    Isabelle Dierckx de Casterlé, Sabine Fevery, Omer Rutgeerts, Caroline Lenaerts, Mark Waer, An D. Billiau & Ben Sprangers

  2. Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium

    Fariba Poosti & Sofie Struyf

  3. Department of Nephrology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Ben Sprangers

Authors
  1. Isabelle Dierckx de Casterlé
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  2. Sabine Fevery
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  3. Omer Rutgeerts
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  4. Fariba Poosti
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  7. Mark Waer
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  8. An D. Billiau
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  9. Ben Sprangers
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Contributions

IDC designed and performed the experiments; acquired, analyzed, and interpreted the data, and wrote the manuscript. OR and CL provided technical support in performing the experiments, and revised the manuscript. SF acquired flow cytometric data, participated in the interpretation of the data, and revised the manuscript. FP and SS provided help in immunofluorescence stainings on tumor tissue. MW, ADB, and BS conceived and supervised the study, contributed to the design of the experiments and interpretation of the data, and reviewed and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ben Sprangers.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the studies involving animals were ethically approved by the KU Leuven Animal Ethics Committee (Project approval number: P256/2014), and were in accordance with the ethical standards and guidelines of the KU Leuven. Animal care was in accordance with the KU Leuven guidelines for laboratory animals. All animals were obtained from external specialized companies (Envigo and Janvier Labs).

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Dierckx de Casterlé, I., Fevery, S., Rutgeerts, O. et al. Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras. Cancer Immunol Immunother 67, 589–603 (2018). https://doi.org/10.1007/s00262-017-2114-8

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