Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells

摘要: Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immunosuppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate and promote antitumor immunity. Our previous study also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive cells, thereby suppressing glioma development in mice. We therefore hypothesized a combinatory strategy modulate via two distinct pathways, i.e., CD40/CD40L stimulation COX-2 blockade, would enhance anti-glioma used three different mouse models evaluate therapeutic effects underlying mechanisms combination regimen with an agonist mAb the inhibitor celecoxib. Treatment glioma-bearing mice therapy significantly prolonged survival compared either anti-CD40 or celecoxib alone. The promoted maturation CD11b(+) both spleen brain, enhanced Cxcl10 while Arg1 CD11b(+)Gr-1(+) brain. Anti-glioma activity was T-cell dependent because depletion CD4(+) CD8(+) vivo abrogated effects. Furthermore, increased frequency T-cells, IFN-γ-production reduced CD4(+)CD25(+)Foxp3(+) T regulatory induced tumor-antigen-specific responses lymph nodes. findings suggest enhances activities promotion type-1 immunity T-cells.