- Poster presentation
- Open Access
Dual-targeting nanoparticles for reprogrammed T cell responses in the tumor microenvironment
© Kosmides and Schneck; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
One of the largest obstacles in cancer immunotherapy involves overcoming the immunosuppressive tumor microenvironment . While many therapies are focused primarily on activating antigen-specific CD8+ T cells, the tumor microenvironment often expresses immunosuppressive cytokines and other immunoregulatory proteins such as checkpoint blockade molecules that diminish their effects . Programmed death ligand 1 (PD-L1) is an inhibitory checkpoint molecule upregulated on many cancers, including melanoma, ovarian cancer, and renal cancer . This can shield a tumor from immune attack by binding to its receptor, PD-1, on T cells. We have developed a nanoparticle platform that combines blockade of PD-L1 with the T cell co-stimulatory signal, anti-4-1BB. This dual targeting system redirects effector cells to recognize target cells while simultaneously blocking checkpoint inhibitors. Antagonistic anti-PD-L1 antibodies and agonistic anti-4-1BB antibodies are conjugated to the surface of biocompatible 50-100 nm iron dextran nanoparticles. The nanoparticles cause a 6-fold increase in IFN-γ production by CD8+ T cells with an exhausted phenotype in the presence of tumor cells in vitro. Additionally, we have shown tumor suppression and a 30% decrease of PD-1 expression in tumor infiltrating lymphocytes in an in vivo B16 mouse melanoma model. This approach may not only reprogram local signaling within the tumor microenvironment, but also promote polyclonal cytotoxic T cell responses in the absence of defining the antigenic specificity of the infiltrating T cells.
- Rabinovich GA, Gabrilovich D, Sotomayor EM: Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007, 25: 267-96. 10.1146/annurev.immunol.25.022106.141609.PubMed CentralView ArticlePubMedGoogle Scholar
- Freeman GJ, Sharpe AH, Kuchroo VK: Protect the killer: CTLs need defenses against the tumor. Nat Med. 2002, 8: 787-9. 10.1038/nm0802-787.View ArticlePubMedGoogle Scholar
- Kamphorst AO, Ahmed R: Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol. 2013, 1-8.Google Scholar
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