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

Abstract

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.

Keywords

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

Abbreviations

APCs

Antigen-presenting cells

Arg1

Arginase 1

BILs

Brain-infiltrating leukocytes

BLI

Bioluminescence imaging

Cxcl10

C-X-C motif chemokine 10

COX-2

Cyclooxygenase-2

Foxp3

Forkhead box P3

gp100

Glycoprotein 100

IFN-γ

Interferon-gamma

IgG

Immunoglobulin G

IL

Interleukin

i.p.

Intraperitoneally

mAb

Monoclonal antibody

MDSCs

Myeloid-derived suppressor cells

MHC

Major histocompatibility complex

NO

Nitric oxide

OVA

Ovalbumin

PGE2

Prostaglandin E2

SB

Sleeping Beauty

TAMs

Tumor-associated macrophages

TNF

Tumor necrosis factor

WT

Wild-type

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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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