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Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Jan 19; Vol. 113 (3), pp. E319-27. Date of Electronic Publication: 2016 Jan 04. - Publication Year :
- 2016
-
Abstract
- Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that dual aOX40 (anti-CD134)/aCTLA-4 (anti-cytotoxic T-lymphocyte-associated protein 4) immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promoting their maximal expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205 (dendritic and epithelial cells, 205 kDa)-HER2 (human epidermal growth factor receptor 2) had significantly improved survival in a mammary carcinoma model. Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment. Furthermore, this therapy was associated with extensive tumor destruction and T-cell infiltration into the tumor. Notably, in a spontaneous model of prostate adenocarcinoma, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen. Collectively, these data demonstrate that the addition of a vaccine with combined aOX40/aCTLA-4 immunotherapy augmented antitumor CD8 T-cell function while limiting Th2 polarization in CD4 cells and improved overall survival.
- Subjects :
- Animals
CD8-Positive T-Lymphocytes immunology
Cell Line
Cell Polarity
Cell Proliferation
Combined Modality Therapy
Female
Immunologic Memory
Immunotherapy
Male
Mammary Neoplasms, Animal immunology
Mammary Neoplasms, Animal pathology
Mammary Neoplasms, Animal therapy
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms pathology
Prostatic Neoplasms immunology
Prostatic Neoplasms pathology
Prostatic Neoplasms therapy
Receptors, OX40 metabolism
Survival Analysis
Th2 Cells cytology
CTLA-4 Antigen immunology
Clonal Anergy immunology
Neoplasms immunology
Neoplasms therapy
Receptor, ErbB-2 immunology
Receptors, OX40 agonists
Vaccination
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 26729864
- Full Text :
- https://doi.org/10.1073/pnas.1510518113