STING Activation as an Immunotherapeutic Strategy for Soft Tissue Sarcoma

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dc.contributor.advisorMonument, Michael J.
dc.contributor.advisorJirik, Frank Robert
dc.contributor.authorMarritt, Kayla Lynn
dc.contributor.committeememberKrawetz, Roman J.
dc.contributor.committeememberYipp, Bryan G.
dc.date2020-11
dc.date.accessioned2020-06-08T22:55:28Z
dc.date.available2020-06-08T22:55:28Z
dc.date.issued2020-06-02
dc.description.abstractImmunotherapy is an emerging field of cancer treatment that is transforming the management of numerous human cancers. However, there remains a substantial proportion of cancer subtypes that are unresponsive to many modern immunotherapy strategies. Soft tissue sarcomas (STS) are aggressive, connective-tissue derived solid cancers and are notoriously resistant to systemic therapies including immunotherapy. Immunologically, sarcomas are frequently characterized by a paucity of lymphocytic infiltrates, an immune suppressive microenvironment, and resistance to immunotherapies such as immune checkpoint inhibition and oncolytic viruses. Activation of the STING (stimulator of interferon genes) pathway can induce potent innate and adaptive anti-tumour immune responses within immunogenic solid tumours. However, this approach has never been tried in immune-inert sarcomas. Herein, STING activation in STS was analyzed to determine if STING activation could induce therapeutic anti-tumour effects and promote anti-tumour immunity. The long-term therapeutic responses of STING activation via 5,6-dimethylxanthenone-4-acetic acid (DMXAA) injection were assessed using a syngeneic murine model of undifferentiated pleomorphic sarcoma (UPS). Intratumoural DMXAA resulted in a durable cure in 50-60% of UPS-bearing mice. Flow cytometry was used to quantify immune infiltration after STING activation treatment and a higher proportion of CD8+/CD3+ cells was observed seven days post DMXAA treatment compared to the vehicle control treatment. Surviving mice all rejected UPS re-challenge in both the extremity and lung, and the therapeutic effects of DMXAA were mitigated by lymphocyte deficiency suggesting adaptive immunologic pathways are integral to the therapeutic response. This data suggests modulation of the STING pathway can elicit local and systemic anti-tumour immune responses in UPS and deserves further consideration as a novel local and systemic treatment for sarcomas.en_US
dc.identifier.citationMarritt, K. L. (2020). STING Activation as an Immunotherapeutic Strategy for Soft Tissue Sarcoma (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37899
dc.identifier.urihttp://hdl.handle.net/1880/112158
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectCancer immunotherapyen_US
dc.subjectStimulator of interferon genes (STING)en_US
dc.subjectCyclic dinucleotidesen_US
dc.subject5,6-dimethylxanthenone-4-acetic acid (DMXAA)en_US
dc.subjectSarcomaen_US
dc.subjectUndifferentiated pleomorphic sarcoma (UPS)en_US
dc.subjectIntratumouralen_US
dc.subjectLymphocytesen_US
dc.subjectPre-clinical modelen_US
dc.subjectSyngeneicen_US
dc.subject.classificationOncologyen_US
dc.titleSTING Activation as an Immunotherapeutic Strategy for Soft Tissue Sarcomaen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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