The Role of the cGAS-STING Pathway in Cancer and Autoimmunity

The DNA sensor cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA derived from infections, cancer, or aberrant self-DNA accumulation. DNA-bound cGAS synthesizes cGAMP, which activates the stimulator of interferon genes (STING) protein to induce type I interferons, inflammatory cytokines, and autophagy. The cGAS-STING pathway played a critical role in cancer immune surveillance by detecting tumor-derived DNA. Furthermore, stimulating the pathway using STING agonists conferred antitumor effects in preclinical tumor models. The induction of type I interferons through the transcription factor IRF3 is considered a major outcome of STING activation that drives immune responses against tumors, but the roles of IFN-independent functions of STING in cancer are not well understood. Here, I generated STING mouse strains with mutations that confer selective loss of STING functions. Using these STING-mutant mice, I show that TBK1 recruitment to STING promotes antitumor effects that are both type I interferon-dependent and -independent. In addition, using mice with selective deletion of the cGAS genes in specific immune cells, I show that dendritic cells, but not macrophages, are responsible for the cancer immune surveillance. By staining intracellular cGAMP, I show that tumor-infiltrating immune cells with greater pinocytosis ability take up cGAMP efficiently. When aberrantly activated, the cGAS-STING pathway can lead to autoimmune diseases. cGAS was responsible for the autoimmunity in mice deficient in intracellular DNase and was shown to be activated in some SLE patients. In order to develop a therapeutic strategy targeting cGAS-mediated autoimmune diseases, I tested if the AAV-CRISPR system targeting the cGAS gene can confer a therapeutic effect in TREX1-deficient mice. In addition, I tested if cGAS drives disease pathogenesis in a mouse SLE model, which closely mimics the human SLE disease. Furthermore, I designed an ImageStream assay to detect the activation of the cGAS-STING pathway in SLE patient PBMCs. In addition to the role in diseases, I observed cell-specific functions of the cGAS-STING pathway in promoting the endosome-to-cytosol protein delivery and mediating T cell death. Altogether, these results improve our understanding of the role of the cGAS-STING pathway in cancer and autoimmune diseases.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Immunology

Grantor

UT Southwestern Medical Center

Year dc:date.issued

2021

Author dc:creator

• Yum, Seoyun

Advisor dc:contributor.advisor

• Hooper, Lora V.

Committee members dc:contributor.committeemember

• Cobb, Melanie H.
• Fu, Yang-Xin
• Chen, Zhijian J.

• Immunologic Surveillance
• Membrane Proteins
• Neoplasms
• NF-kappa B
• Protein Serine-Threonine Kinases

Language dc:language.iso

en

Identifier

1381370424

OAI record oai:identifier

https://utswmed-ir.tdl.org/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Autswmed-ir.tdl.org%3A2152.5%2F10090