Abstract
CD40 ligand (CD40L) is a potent stimulator of tumor immunity via its activation of dendritic cells, which in turn initiate T-cell activation. However, T cells are inhibited by suppressive myeloid cells, which constitute an important part of immune evasion. We hypothesized that CD40L may revert the function of suppressive myeloid cells to generate a T-cell stimulatory environment, and this was investigated in the murine bladder cancer model MB49/C57BL/6. Upon intratumoral adenoviral CD40L (AdCD40L) gene therapy, the infiltration of CD11b+Gr-1+ cells was significantly reduced, whereas activated T cells were increased. In vitro, CD40L-expressing MB49 cells tilted the myeloid subpopulations in favor of granulocytic CD11b+Gr-1high myeloid cells instead of monocytic CD11b+Gr-1int/low myeloid cells. Further, the level of macrophages in splenocyte co-cultures with MB49 cells was evaluated. In cultures with MB49 cells expressing CD40L, the overall level of macrophages was reduced and the remaining cells were differentiated into M1-like cells. Hence, these data support that CD40L tilts myeloid immune cell populations in favor of anti-tumor immunity (M1) instead of immunosuppression (CD11b+Gr-1int/low and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue.
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Acknowledgements
We thank Liye Chen at the Uppsala University for helpful assistance. The project was financed by grants to AL from the Swedish Cancer Society, the Swedish Research Council, the EU FP6/Apotherapy, AFA Insurance AB, ALF Uppsala University Hospital funding and the Medical Faculty at the Uppsala University.
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AL and SMM have a royalty agreement with Alligator Bioscience AB. Further, AL is the CEO of Lokon Pharma AB and a scientific advisor at NEXTTOBE AB. The other authors declare no conflict of interest.
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Liljenfeldt, L., Dieterich, L., Dimberg, A. et al. CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes. Cancer Gene Ther 21, 95–102 (2014). https://doi.org/10.1038/cgt.2014.2
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DOI: https://doi.org/10.1038/cgt.2014.2
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