Cancer Immunology, Immunotherapy

, Volume 63, Issue 8, pp 847–857 | Cite as

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

Original Article


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


Glioma Agonistic anti-CD40 mAb Celecoxib Type-1 immunity Myeloid cells COX-2 



Antigen-presenting cells


Arginase 1


Brain-infiltrating leukocytes


Bioluminescence imaging


C-X-C motif chemokine 10




Forkhead box P3


Glycoprotein 100




Immunoglobulin G






Monoclonal antibody


Myeloid-derived suppressor cells


Major histocompatibility complex


Nitric oxide




Prostaglandin E2


Sleeping Beauty


Tumor-associated macrophages


Tumor necrosis factor





Grant Supports from: The National Institutes of Health (NIH) (2R01 NS055140, 1P01 CA132714) and Musella Foundation for Brain Tumor Research and Information. This project used University of Pittsburgh Cancer Institute (UPCI) shared resources (Animal Facility, In Vivo Imaging Facility and Cytometry Facility) that are supported in part by NIH P30CA047904. The authors thank Dr. Gary Kohanbash and Maki Ikeura (University of Pittsburgh) for their administrative assistance.

Conflict of interest

The authors have no financial conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Akemi Kosaka
    • 1
    • 2
    • 3
  • Takayuki Ohkuri
    • 1
    • 2
    • 3
  • Hideho Okada
    • 4
    • 5
    • 6
  1. 1.Brain Tumor ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Department of Neurological SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.G.1 Research PavilionHillman Cancer CenterPittsburghUSA
  4. 4.Brain Tumor and Cancer Immunology ProgramsUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.Departments of Neurological Surgery, Surgery and ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  6. 6.1.19e Research Pavilion at the Hillman Cancer CenterPittsburghUSA

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