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Combined targeting of co-stimulatory (OX40) and co-inhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust anti-tumor immunity

Ligation of the TNF receptor family co-stimulatory molecule OX40 (CD134) with an agonist anti-OX40 mAb enhances anti-tumor immunity by augmenting T cell differentiation as well as turning off the suppressive activity of FoxP3+CD4+ regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor, CTLA-4, releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents can have limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the combination of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell-dependent manner. Mechanistic studies revealed that combination immunotherapy directed the expansion of effector T-bethigh/Eomeshigh granzyme B+ CD8 T cells. Dual immunotherapy also induced among distinct populations of Th1 (IL-2, IFN-γ) and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents.

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Correspondence to William L Redmond.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Murine Tumor
  • Checkpoint Inhibitor
  • Tumor Immunotherapy
  • Combination Immunotherapy
  • Combine Target