CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes

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-1 high 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-1 int/low and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue. © 2014 Nature America, Inc. All rights reserved.