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Recipient leukocyte infusion enhances the local and systemic graft-versus-neuroblastoma effect of allogeneic bone marrow transplantation in mice

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Abstract

Allogeneic hematopoietic stem cell transplantation and donor leukocyte infusion (DLI) may hold potential as a novel form of immunotherapy for high-risk neuroblastoma. DLI, however, carries the risk of graft-versus-host disease (GvHD). Recipient leukocyte infusion (RLI) induces graft-versus-leukemia responses without GvHD in mice and is currently being explored clinically. Here, we demonstrate that both DLI and RLI, when given to mixed C57BL/6 → A/J radiation chimeras carrying subcutaneous Neuro2A neuroblastoma implants, can slow the local growth of such tumors. DLI provoked full donor chimerism and GvHD; RLI produced graft rejection but left mice healthy. Flow cytometric studies showed that the chimerism of intratumoral leukocytes paralleled the systemic chimerism. This was associated with increased CD8/CD4 ratios, CD8+ T-cell IFN-γ expression and NK-cell Granzyme B expression within the tumor, following both DLI and RLI. The clinically safe anti-tumor effect of RLI was further enhanced by adoptively transferred naïve recipient-type NK cells. In models of intravenous Neuro2A tumor challenge, allogeneic chimeras showed superior overall survival over syngeneic chimeras. Bioluminescence imaging in allogeneic chimeras challenged with luciferase-transduced Neuro2A cells showed both DLI and RLI to prolong metastasis-free survival. This is the first experimental evidence that RLI can safely produce a local and systemic anti-tumor effect against a solid tumor. Our data indicate that RLI may provide combined T-cell and NK-cell reactivity effectively targeting Neuro2A neuroblastoma.

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Acknowledgments

This study was supported by Grant G.0540.10N from the Flanders National Fund for Scientific Research. Leen Willems is a doctoral student of the Flanders Fund for Scientific Research.

Conflict of interest

The authors have no relevant financial conflict of interest to disclose.

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Authors and Affiliations

  1. Laboratory of Experimental Transplantation, KU Leuven, Herestraat 49, box 811, 3000, Leuven, Belgium

    Leen Willems, Sabien Fevery, Ben Sprangers, Omer Rutgeerts, Caroline Lenaerts, Mark Waer & An D. Billiau

  2. Department of Pediatrics, University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium

    Leen Willems & Stefaan Van Gool

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

    Ben Sprangers

  4. Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Kapucijnenvoer 33, 3000, Leuven, Belgium

    Abdelilah Ibrahimi & Rik Gijsbers

  5. Laboratory of Pediatric Immunology, KU Leuven, Herestraat 49, box 811, 3000, Leuven, Belgium

    Stefaan Van Gool

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  1. Leen Willems
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  2. Sabien Fevery
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Correspondence to Leen Willems.

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Willems, L., Fevery, S., Sprangers, B. et al. Recipient leukocyte infusion enhances the local and systemic graft-versus-neuroblastoma effect of allogeneic bone marrow transplantation in mice. Cancer Immunol Immunother 62, 1733–1744 (2013). https://doi.org/10.1007/s00262-013-1479-6

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