Recognition of foreign DNA in the cytosol of host cells is critical for the initiation of immune responses to DNA viruses. Recognition of viral DNA activates numerous signaling pathways, including the induction of potent antiviral cytokines such as type I interferons. Although the cytosolic DNA-sensing pathway evolved to detect viruses, our recent preliminary data also suggest that DNA-dependent activation of STING may also be critical in the response to tumors. Here we propose to investigate how recognition of cytosolic DNA leads to activation of anti-tumor and anti-viral responses by Natural Killer (NK) cells. Our overall hypothesis is that cytosolic detection of DNA is a common mechanism underlying innate recognition of viruses and tumors by NK cells. We describe three Aims that will illuminate how the cGAS-STING pathway initiates anti-viral and anti-tumor responses.
These Aims represent a close collaboration between the Raulet Lab, which has expertise in NK cells and the NKG2D activating receptor, and the lab of consultant Russell Vance, which has expertise in cytosolic DNA sensing and the STING pathway.
The Aims are as follows: (1) Determine how the cGAS-STING pathway activates NK cells and other immune cells in vivo. Our preliminary data show that STING engagement by HSV-1 or synthetic 2'3'-cGAMP activates NK cells and other immune cells in vivo. STING activation leads to production of type I IFN, STAT6-dependent chemokines, and activation of NKG2D ligands. The mechanisms linking these pathways to NK activation, and the cell types involved, will be determined in vivo using various knockout mice. (2) Determine if cGAS-STING signaling is required for innate immune control of tumors. Mice harboring an E?-myc transgene, which develop B cell lymphomas, will be crossed to mice deficient in the cGAS-STING signaling pathway. We will determine whether loss of cGAS-STING accelerates tumorigenesis in this model. We hypothesize that cGAS-STING signaling is required for tumor cell and possibly APC expression of ligands that activate NK cell receptors (e.g., NKG2D and DNAM1). (3) Determine the mechanisms by which DNA damage leads to accumulation of cytosolic DNA. Our preliminary data indicate that cells experiencing DNA damage or undergoing transformation exhibit increased and aberrant accumulation of cytosolic DNA derived largely from endogenous retroviruses/elements. In this Aim we will assess whether increased cytosolic DNA is due to increased expression of retrovirus/element RNA, and/or increased cytosolic reverse transcriptase activity, and/or decreased activity of cytosolic DNA exonucleases (e.g., TREX1).

Public Health Relevance

Recognition of cytosolic DNA is an important mechanism by which innate immune responses to viruses and tumors are initiated. We expect that developing a better understanding of how recognition of foreign and self DNA leads to immune activation will allow the development of improved immunotherapeutics and vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunity and Host Defense Study Section (IHD)
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Miller, Lara R
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University of California Berkeley
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Marcus, Assaf; Mao, Amy J; Lensink-Vasan, Monisha et al. (2018) Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity 49:754-763.e4
Hsu, Joy; Hodgins, Jonathan J; Marathe, Malvika et al. (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest 128:4654-4668
Kerdiles, Yann M; Almeida, Francisca F; Thompson, Thornton et al. (2017) Natural-Killer-like B Cells Display the Phenotypic and Functional Characteristics of Conventional B Cells. Immunity 47:199-200
Vance, Russell E; Eichberg, Michael J; Portnoy, Daniel A et al. (2017) Listening to each other: Infectious disease and cancer immunology. Sci Immunol 2:
Raulet, David H; Marcus, Assaf; Coscoy, Laurent (2017) Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells. Immunol Rev 280:93-101
Clark, Sarah E; Filak, Holly C; Guthrie, Brandon S et al. (2016) Bacterial Manipulation of NK Cell Regulatory Activity Increases Susceptibility to Listeria monocytogenes Infection. PLoS Pathog 12:e1005708
Greene, Trever T; Tokuyama, Maria; Knudsen, Giselle M et al. (2016) A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression. Elife 5:
Bose, Debojit; Su, Yichi; Marcus, Assaf et al. (2016) An RNA-Based Fluorescent Biosensor for High-Throughput Analysis of the cGAS-cGAMP-STING Pathway. Cell Chem Biol 23:1539-1549
Iannello, Alexandre; Thompson, Thornton W; Ardolino, Michele et al. (2016) Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr Opin Immunol 38:52-8
Raulet, David H (2015) Bone Marrow Cell Rejection, MHC, NK Cells, and Missing Self Recognition: Ain't That Peculiar (with Apologies to Marvin Gaye). J Immunol 195:2923-5

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