Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNγ is mediated by both CD8+ and CD4+ T-cells

Authors

  • Karin Enell Smith,

    Corresponding author
    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
    • Glioma Immunotherapy Group, The Rausing Laboratory, BMC D14, SE-221 84 Lund, Sweden
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    • Fax: +46 46 2224606.

  • Sara Fritzell,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Wiaam Badn,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Sofia Eberstål,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Shorena Janelidze,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Edward Visse,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Anna Darabi,

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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  • Peter Siesjö

    1. Department of Clinical Sciences, Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, BMC D14, Lund University, SE-221 84 Lund, Sweden
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Abstract

We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNγ of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNγ systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFNγ-producing T-cells, were augmented after immunizations with GM-CSF and IFNγ. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.c.) rechallenges. Depletion of T-cells showed that both CD4+ and CD8+ T-cells were essential for the combined GM-CSF and IFNγ effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFNγ survived. We conclude that the addition of recombinant IFNγ to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors. © 2008 Wiley-Liss, Inc.

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