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Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy.

ABSTRACT: Overcoming the immunosuppressive tumor microenvironment (TME) is critical to realizing the potential of cancer immunotherapy strategies. Agonists of stimulator of interferon genes (STING), a cytosolic immune adaptor protein, have been shown to induce potent anti-tumor activity when delivered into the TME. However, the anionic properties of STING agonists make them poorly membrane permeable, and limit their ability to engage STING in the cytosol of responding cells. In this study, cationic liposomes with varying surface polyethylene glycol (PEG) levels were used to encapsulate cGAMP to facilitate its cytosolic delivery. In vitro studies with antigen-presenting cells (APCs) revealed that liposomal formulations substantially improved the cellular uptake of cGAMP and pro-inflammatory gene induction relative to free drug. Liposomal encapsulation allowed cGAMP delivery to metastatic melanoma tumors in the lung, leading to anti-tumor activity, whereas free drug produced no effect at the same dose. Injection of liposomal cGAMP into orthotopic melanoma tumors showed retention of cGAMP at the tumor site and co-localization with tumor-associated APCs. Liposomal delivery induced regression of injected tumors and produced immunological memory that protected previously treated mice from rechallenge with tumor cells. These results show that liposomal delivery improves STING agonist activity, and could improve their utility in clinical oncology.

SUBMITTER: Koshy ST

PROVIDER: S-EPMC6152940 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy.

Koshy Sandeep T ST Cheung Alexander S AS Gu Luo L Graveline Amanda R AR Mooney David J DJ

Advanced biosystems 20170105 1-2

Overcoming the immunosuppressive tumor microenvironment (TME) is critical to realizing the potential of cancer immunotherapy strategies. Agonists of stimulator of interferon genes (STING), a cytosolic immune adaptor protein, have been shown to induce potent anti-tumor activity when delivered into the TME. However, the anionic properties of STING agonists make them poorly membrane permeable, and limit their ability to engage STING in the cytosol of responding cells. In this study, cationic liposo ...[more]

PMID: 30258983

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Project description:Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance. In addition, a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo experiments, we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.Electronic supplementary materialSupplementary material (synthesis of CDGSF, 522, PC7A and OVA; preparation of MCNVs; representative gating strategies for flow cytometry) is available in the online version of this article at 10.1007/s12274-022-4282-x.

Dataset Information

Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy.

Publications

Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy.

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