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Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy

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Abstract

In the past decade, remarkable progress has been made in immunotherapy against cancer. Specifically, the introduction of immune checkpoint inhibitors has revolutionized the field. However, many patients are unable to benefit significantly from this treatment option. One of the major reasons for this is most likely the absence of an adequate tumor-specific T cell response in these patients. A way to circumvent this problem might be to combine immune checkpoint inhibitor treatment with new strategies to activate tumor-specific T cells. One such strategy could be to activate and mature dendritic cells in situ. Dendritic cells carry an array of external and internal pattern recognition receptors that induce cell activation and maturation when interacting with their corresponding damage-associated or pathogen-associated molecular patterns (DAMPs or PAMPs). Targeting such molecular patterns directly to dendritic cells might be a way to evoke stronger immune responses. Here, we review our recent findings using antibody-targeted DNA. We summarize the results from our experiments showing that dendritic cells can be actively targeted in vivo through the αXβ2 integrin subunit CD11c, and that DNA delivered through this receptor in vitro leads to maturation of dendritic cells via the cytosolic cGAS/STING DNA-sensing pathway.

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Abbreviations

cDC1:

Classical type 1 dendritic cell

cDC2:

Classical type 2 dendritic cell

CDN:

Cyclic di-nucleotide

cGAMP:

Cyclic GMP–AMP

cGAS:

Cyclic GMP–AMP synthase

CR4:

Complement receptor 4

DAMP:

Damage-associated molecular pattern

ER:

Endoplasmic reticulum

IRF3:

Interferon regulatory factor 3

moDC:

Monocyte-derived dendritic cell

PAMP:

Pathogen-associated molecular pattern

pDC:

Plasmacytoid dendritic cell

PRR:

Pattern recognition receptor

STING:

Stimulator of interferon genes

TBK1:

TANK-binding kinase 1

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Funding

The support for our research from The Danish Cancer Society (Grant No. A10193), Dansk Kræftforskningsfond, The Andersen-Isted Foundation, The Else og Mogens Wedell-Wedellsborgs Foundation, Familien Erichsens Mindefond, Fabrikant Einar Willumsens Mindefond and The Pedersen Charity Foundation, Vaduz, Liechtenstein is gratefully acknowledged.

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Authors and Affiliations

  1. Laboratory of Immunology, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3B, 9220, Aalborg, Denmark

    Marlene Fyrstenberg Laursen, Emil Kofod-Olsen & Ralf Agger

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  1. Marlene Fyrstenberg Laursen
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  2. Emil Kofod-Olsen
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  3. Ralf Agger
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Marlene Fyrstenberg Laursen, Emil Kofod-Olsen and Ralf Agger all contributed equally to the writing of the manuscript.

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Correspondence to Ralf Agger.

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Fyrstenberg Laursen, M., Kofod-Olsen, E. & Agger, R. Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy. Cancer Immunol Immunother 68, 1875–1880 (2019). https://doi.org/10.1007/s00262-019-02400-1

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