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An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases
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An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases
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Journal Article
An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases
2019
Overview
Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate–adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge.
Successful anticancer immunotherapy should induce robust systemic immunity against metastases. Here, the authors engineer an inhalable nano-STING agonist, which synergizes with fractionated radiation to control lung metastases and confers long-term systemic antitumor immunity in mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/51
/ 14
/ 14/5
/ 14/63
/ 38
/ 38/22
/ 38/88
/ 38/90
/ 42
/ 59
/ Agonists
/ AMP
/ Animals
/ Antigen-Presenting Cells - drug effects
/ Antigen-Presenting Cells - immunology
/ Antigens
/ Cancer
/ Dendritic Cells - drug effects
/ Dendritic Cells - immunology
/ Humanities and Social Sciences
/ Immunity
/ Interferon Type I - drug effects
/ Interferon Type I - immunology
/ Lungs
/ Melanoma, Experimental - secondary
/ Membrane Proteins - agonists
/ Mice
/ Nucleotides, Cyclic - administration & dosage
/ Nucleotides, Cyclic - pharmacology
/ Science
/ Survival
/ Tumors
