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Dual-targeting nanoparticles for reprogrammed T cell responses in the tumor microenvironment

One of the largest obstacles in cancer immunotherapy involves overcoming the immunosuppressive tumor microenvironment [1]. 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 [2]. Programmed death ligand 1 (PD-L1) is an inhibitory checkpoint molecule upregulated on many cancers, including melanoma, ovarian cancer, and renal cancer [3]. 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.

References

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    Kamphorst AO, Ahmed R: Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol. 2013, 1-8.

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Correspondence to Alyssa K Kosmides.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Keywords

  • Melanoma
  • Tumor Microenvironment
  • Tumor Infiltrate Lymphocyte
  • Checkpoint Inhibitor
  • Iron Dextran