CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes.
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-1(high) myeloid cells instead of monocytic CD11b(+)Gr-1(int/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-1(int/low) and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden.
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Liljenfeldt
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden.
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Dieterich
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden.
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Dimberg
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden.
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Mangsbo
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden.
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0000000185836138
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Loskog
D000818:Animals; D023201:CD40 Ligand / Q000276:immunology / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology
D023201:CD40 Ligand