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Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth.

ABSTRACT: We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. Immunoswitch particles enhance effector-target cell conjugation and bypass the requirement for a priori knowledge of tumor antigens. The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells. Changes in the T cell receptor repertoire against a single tumor antigen indicate immunoswitch particles expand an effective set of T cell clones. Our data show the potential of a signal-switching approach to cancer immunotherapy that simultaneously targets two stages of the cancer immunity cycle resulting in robust antitumor activity.

SUBMITTER: Kosmides AK

PROVIDER: S-EPMC8635119 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth.

Kosmides Alyssa K AK Sidhom John-William JW Fraser Andrew A Bessell Catherine A CA Schneck Jonathan P JP

ACS nano 20170607 6

We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or n ...[more]

PMID: 28589725

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Project description:BackgroundImmune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration.MethodsThe particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments.ResultsHere, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1-6 cells. We found that the drug-treated Hepa1-6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer.ConclusionOur results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition.

Dataset Information

Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth.

Publications

Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth.

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