Title |
Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity
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Published in |
Cancer Immunology Research, February 2014
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DOI | 10.1158/2326-6066.cir-13-0031-t |
Pubmed ID | |
Authors |
William L. Redmond, Stefanie N. Linch, Melissa J. Kasiewicz |
Abstract |
Ligation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the 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 has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration 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 the combination immunotherapy directed the expansion of effector T-bet(high)/Eomes(high) granzyme B(+) CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (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 the 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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Geographical breakdown
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France | 1 | <1% |
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Unknown | 129 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 32 | 24% |
Student > Ph. D. Student | 22 | 17% |
Student > Bachelor | 14 | 11% |
Student > Master | 14 | 11% |
Other | 11 | 8% |
Other | 18 | 14% |
Unknown | 22 | 17% |
Readers by discipline | Count | As % |
---|---|---|
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Immunology and Microbiology | 23 | 17% |
Biochemistry, Genetics and Molecular Biology | 18 | 14% |
Engineering | 6 | 5% |
Other | 12 | 9% |
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