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Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA

Cancer Gene Therapy volume 31, pages 28–42 (2024)Cite this article

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Abstract

Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress anti-tumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This finding was unexpected given previous reports that type I interferon alpha (IFN-α) inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with type I interferon beta (IFN-β) upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), a hub adaptor protein through which multiple dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has also been associated with multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This finding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells.

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Fig. 1: dsDNA increases CCL22 in epithelial cancer cells.
Fig. 2: STING is essential for CCL22 upregulation in response to dsDNA.
Fig. 3: STING agonist 2’3’-cGAM(PS)2(Rp/Sp) and dsDNA upregulate CCL22 in a manner dependent on TBK1/IKKε.
Fig. 4: NF-κB contributes minimally to CCL22 upregulation by dsDNA.
Fig. 5: IRF3 is indispensable for CCL22 upregulation in response to dsDNA.
Fig. 6: Two strains of HeLa cells differ dramatically in upregulation of CCL22 by dsDNA.
Fig. 7: Simplified schematic of the cGAS/STING signaling cascade.

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Data availability

All data were reported in the figures. The HeLa cell line used in this study that was obtained from the Kazazian and Moran laboratories through Dr. Anthony Furano at NIDDK will be made available upon request.

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Acknowledgements

We wish to thank Dr. James Drummond and Dr. Robert McKallip for their helpful suggestions during the course of the study. We also thank Dr. James Drummond and Dr. Angabin Matin for their constructive comments to improve the manuscript.

Funding

This work was supported by startup funds and a Dean’s Seed Grant from Mercer University School of Medicine, Macon GA, USA.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA

    Jihyun Kim, Jocelyn V. Pena, Hannah P. McQueen, Lingwei Kong, Dina Michael, Elmira M. Lomashvili & Pamela R. Cook

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  1. Jihyun Kim
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Contributions

JK: conceptualization, experimentation, supervision, writing (review and editing). JVP: experimentation, supervision, writing (review and editing). HPMQ: experimentation. LK: experimentation, supervision, writing (review and editing). EML: experimentation. DM: experimentation. PRC: conceptualization, methodology, analysis, experimentation, supervision, writing (original draft and revision).

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Correspondence to Pamela R. Cook.

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Kim, J., Pena, J.V., McQueen, H.P. et al. Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA. Cancer Gene Ther 31, 28–42 (2024). https://doi.org/10.1038/s41417-023-00678-z

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