Blockade of Programmed Death Ligand 1 Enhances the Therapeutic Efficacy of Combination Immunotherapy against Melanoma
Open Access
- 1 April 2010
- journal article
- Published by The American Association of Immunologists
- Vol. 184 (7), 3442-3449
- https://doi.org/10.4049/jimmunol.0904114
Abstract
Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1. PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DCs) and B16 melanoma. In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-γ production and cytotoxicity by Ag-specific T cells. In vivo, the systemic administration of anti–PD-L1 Ab plus melanoma peptide-pulsed DCs resulted in a higher number of melanoma peptide-specific CD8+ T cells, but this combination was insufficient to delay the growth of established B16 melanoma. Although the addition of 600 rad of total body irradiation delayed tumor growth, further adoptive transfer of Ag-specific CD8+ T cells was needed to achieve tumor regression and long-term survival of the treated mice. Lymphopenic mice treated with anti–PD-L1 Ab demonstrated increased activation and persistence of adoptively transferred T cells, including a higher number of CD8+ T cells infiltrating the tumor mass. Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma.Keywords
This publication has 35 references indexed in Scilit:
- TLR3-Stimulated Dendritic Cells Up-regulate B7-H1 Expression and Influence the Magnitude of CD8 T Cell Responses to Tumor VaccinationThe Journal of Immunology, 2009
- PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia modelBlood, 2009
- Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impairedBlood, 2009
- Impaired negative regulation of homeostatically proliferating T cellsBlood, 2009
- Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infectionThe Journal of Experimental Medicine, 2008
- Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferationThe Journal of Experimental Medicine, 2007
- Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell ResponsesImmunity, 2007
- Tissue expression of PD-L1 mediates peripheral T cell toleranceThe Journal of Experimental Medicine, 2006
- Augmentation of antitumor immune responses after adoptive transfer of bone marrow derived from donors immunized with tumor lysate-pulsed dendritic cellsTransplantation and Cellular Therapy, 2004
- Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor LymphocytesScience, 2002