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PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors
- Source :
- Proceedings of the National Academy of Sciences of the United States. March 2, 2010, Vol. 107 Issue 9, p4275, 6 p.
- Publication Year :
- 2010
-
Abstract
- Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or FIt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding [alpha]PD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-y production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-[gamma]/TNF-[alpha] double-producing [CD8.sup.+] T cells within the tumor. These results suggest that combination blockade of the PD-1/ PD-L1-and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory. Flt3-ligand | melanoma | PD-L1 | immunotherapy | vaccine doi/10.1073/pnas.0915174107
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 107
- Issue :
- 9
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.221203633