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Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2014 Feb; Vol. 2 (2), pp. 142-53. Date of Electronic Publication: 2013 Nov 11. - Publication Year :
- 2014
-
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.<br /> (©2013 AACR.)
- Subjects :
- Adoptive Transfer methods
Animals
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Cell Differentiation immunology
Cytokines biosynthesis
Male
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy methods
Neoplasm Transplantation
Prostatic Neoplasms immunology
Sarcoma immunology
T-Lymphocytes, Regulatory immunology
CTLA-4 Antigen immunology
Immunotherapy methods
Prostatic Neoplasms therapy
Receptors, OX40 immunology
Sarcoma therapy
T-Lymphocyte Subsets immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 2
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 24778278
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-13-0031-T