Back to Search
Start Over
Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.
- Source :
-
Cancer research [Cancer Res] 2013 Dec 01; Vol. 73 (23), pp. 6900-12. Date of Electronic Publication: 2013 Aug 23. - Publication Year :
- 2013
-
Abstract
- The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.
- Subjects :
- Animals
B7-H1 Antigen antagonists & inhibitors
B7-H1 Antigen immunology
CD8-Positive T-Lymphocytes physiology
Carcinoma, Ovarian Epithelial
Cells, Cultured
Drug Evaluation, Preclinical
Drug Synergism
Female
Lymphocyte Count
Lymphocytes, Tumor-Infiltrating drug effects
Lymphocytes, Tumor-Infiltrating pathology
Lymphocytes, Tumor-Infiltrating physiology
Mice
Mice, Inbred C57BL
Neoplasms, Glandular and Epithelial mortality
Neoplasms, Glandular and Epithelial pathology
Ovarian Neoplasms mortality
Ovarian Neoplasms pathology
Programmed Cell Death 1 Receptor immunology
Signal Transduction immunology
Antibodies administration & dosage
Antineoplastic Agents administration & dosage
CD8-Positive T-Lymphocytes drug effects
Immunotherapy methods
Neoplasms, Glandular and Epithelial immunology
Neoplasms, Glandular and Epithelial therapy
Ovarian Neoplasms immunology
Ovarian Neoplasms therapy
Programmed Cell Death 1 Receptor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 73
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 23975756
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-13-1550