Pharmacological Activation of cGAS for Cancer Immunotherapy
When compartmentally mislocalized within cells, nucleic acids can be exceptionally immunostimulatory and can even trigger the immune-mediated elimination of cancer. Specifically, the accumulation of double-stranded DNA in the cytosol can efficiently promote antitumor immunity by activating the cGAMP...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:18d4e625fa1744229af759d9c3dd27b12021-12-01T07:43:40ZPharmacological Activation of cGAS for Cancer Immunotherapy1664-322410.3389/fimmu.2021.753472https://doaj.org/article/18d4e625fa1744229af759d9c3dd27b12021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.753472/fullhttps://doaj.org/toc/1664-3224When compartmentally mislocalized within cells, nucleic acids can be exceptionally immunostimulatory and can even trigger the immune-mediated elimination of cancer. Specifically, the accumulation of double-stranded DNA in the cytosol can efficiently promote antitumor immunity by activating the cGAMP synthase (cGAS) / stimulator of interferon genes (STING) cellular signaling pathway. Targeting this cytosolic DNA sensing pathway with interferon stimulatory DNA (ISD) is therefore an attractive immunotherapeutic strategy for the treatment of cancer. However, the therapeutic activity of ISD is limited by several drug delivery barriers, including susceptibility to deoxyribonuclease degradation, poor cellular uptake, and inefficient cytosolic delivery. Here, we describe the development of a nucleic acid immunotherapeutic, NanoISD, which overcomes critical delivery barriers that limit the activity of ISD and thereby promotes antitumor immunity through the pharmacological activation of cGAS at the forefront of the STING pathway. NanoISD is a nanoparticle formulation that has been engineered to confer deoxyribonuclease resistance, enhance cellular uptake, and promote endosomal escape of ISD into the cytosol, resulting in potent activation of the STING pathway via cGAS. NanoISD mediates the local production of proinflammatory cytokines via STING signaling. Accordingly, the intratumoral administration of NanoISD induces the infiltration of natural killer cells and T lymphocytes into murine tumors. The therapeutic efficacy of NanoISD is demonstrated in preclinical tumor models by attenuated tumor growth, prolonged survival, and an improved response to immune checkpoint blockade therapy.Kyle M. GarlandJonah C. RoschCarcia S. CarsonLihong Wang-BishopAnn HannaSema SevimliCasey Van KaerJustin M. BalkoJustin M. BalkoManuel AscanoJohn T. WilsonJohn T. WilsonJohn T. WilsonJohn T. WilsonJohn T. WilsonJohn T. WilsonFrontiers Media S.A.articlecancercGAS/STING pathwayendosomal escapeimmunotherapyinnate immune agonistintratumoralImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
cancer cGAS/STING pathway endosomal escape immunotherapy innate immune agonist intratumoral Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
cancer cGAS/STING pathway endosomal escape immunotherapy innate immune agonist intratumoral Immunologic diseases. Allergy RC581-607 Kyle M. Garland Jonah C. Rosch Carcia S. Carson Lihong Wang-Bishop Ann Hanna Sema Sevimli Casey Van Kaer Justin M. Balko Justin M. Balko Manuel Ascano John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson Pharmacological Activation of cGAS for Cancer Immunotherapy |
| description |
When compartmentally mislocalized within cells, nucleic acids can be exceptionally immunostimulatory and can even trigger the immune-mediated elimination of cancer. Specifically, the accumulation of double-stranded DNA in the cytosol can efficiently promote antitumor immunity by activating the cGAMP synthase (cGAS) / stimulator of interferon genes (STING) cellular signaling pathway. Targeting this cytosolic DNA sensing pathway with interferon stimulatory DNA (ISD) is therefore an attractive immunotherapeutic strategy for the treatment of cancer. However, the therapeutic activity of ISD is limited by several drug delivery barriers, including susceptibility to deoxyribonuclease degradation, poor cellular uptake, and inefficient cytosolic delivery. Here, we describe the development of a nucleic acid immunotherapeutic, NanoISD, which overcomes critical delivery barriers that limit the activity of ISD and thereby promotes antitumor immunity through the pharmacological activation of cGAS at the forefront of the STING pathway. NanoISD is a nanoparticle formulation that has been engineered to confer deoxyribonuclease resistance, enhance cellular uptake, and promote endosomal escape of ISD into the cytosol, resulting in potent activation of the STING pathway via cGAS. NanoISD mediates the local production of proinflammatory cytokines via STING signaling. Accordingly, the intratumoral administration of NanoISD induces the infiltration of natural killer cells and T lymphocytes into murine tumors. The therapeutic efficacy of NanoISD is demonstrated in preclinical tumor models by attenuated tumor growth, prolonged survival, and an improved response to immune checkpoint blockade therapy. |
| format |
article |
| author |
Kyle M. Garland Jonah C. Rosch Carcia S. Carson Lihong Wang-Bishop Ann Hanna Sema Sevimli Casey Van Kaer Justin M. Balko Justin M. Balko Manuel Ascano John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson |
| author_facet |
Kyle M. Garland Jonah C. Rosch Carcia S. Carson Lihong Wang-Bishop Ann Hanna Sema Sevimli Casey Van Kaer Justin M. Balko Justin M. Balko Manuel Ascano John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson John T. Wilson |
| author_sort |
Kyle M. Garland |
| title |
Pharmacological Activation of cGAS for Cancer Immunotherapy |
| title_short |
Pharmacological Activation of cGAS for Cancer Immunotherapy |
| title_full |
Pharmacological Activation of cGAS for Cancer Immunotherapy |
| title_fullStr |
Pharmacological Activation of cGAS for Cancer Immunotherapy |
| title_full_unstemmed |
Pharmacological Activation of cGAS for Cancer Immunotherapy |
| title_sort |
pharmacological activation of cgas for cancer immunotherapy |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/18d4e625fa1744229af759d9c3dd27b1 |
| work_keys_str_mv |
AT kylemgarland pharmacologicalactivationofcgasforcancerimmunotherapy AT jonahcrosch pharmacologicalactivationofcgasforcancerimmunotherapy AT carciascarson pharmacologicalactivationofcgasforcancerimmunotherapy AT lihongwangbishop pharmacologicalactivationofcgasforcancerimmunotherapy AT annhanna pharmacologicalactivationofcgasforcancerimmunotherapy AT semasevimli pharmacologicalactivationofcgasforcancerimmunotherapy AT caseyvankaer pharmacologicalactivationofcgasforcancerimmunotherapy AT justinmbalko pharmacologicalactivationofcgasforcancerimmunotherapy AT justinmbalko pharmacologicalactivationofcgasforcancerimmunotherapy AT manuelascano pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy AT johntwilson pharmacologicalactivationofcgasforcancerimmunotherapy |
| _version_ |
1718405399300800512 |