STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy?

Abstract

DNA has potent immunogenic properties that are useful to enhance vaccine efficacy. DNA also incites hyperinflammation and autoimmunity if DNA sensing is not regulated. Paradoxically, DNA regulates immunity and autoimmunity when administered systemically as DNA nanoparticles. DNA nanoparticles regulated immunity via cytosolic DNA sensors that activate the signaling adaptor stimulator of interferon genes. In this review, we describe how DNA sensing to activate stimulator of interferon genes promotes regulatory responses and discuss the biological and clinical implications of these responses for understanding disease progression and designing better therapies for patients with chronic inflammatory diseases, such as autoimmune syndromes or cancer.

Keywords:

• autoimmunity
• cancer
• DNA
• immunity
• immunotherapy
• nanoparticles
• STING
• tolerance

Financial & competing interests disclosure

H Lemos is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation, the Arthritis Foundation, and the Carlos and Marguerite Mason Trust and the NIH. AL Mellor is a consultant for NewLink Genetics Inc and receives income from this source, Research support from the NIH, the Arthritis Foundation and the Carlos and Marguerite Mason Trust. L Huang is supported by NIH grants and the Carlos and Marguerite Mason Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• DNA is not only an immunogen but also a tolerogen.

• The route and method of DNA delivery are critical factors driving particular immune responses in whole organisms.

• Evaluating responses to DNA by cultured cells is informative but has limited value in predicting immunological responses to DNA in whole organisms and may even be misleading.

• Cytosolic DNA sensors that activate the adaptor stimulator of interferon genes (STING) are expressed by many cell types, greatly expanding the potential of DNA to be sensed to elicit immune responses by stimulating IFN-I production at sites of inflammation.

• Emerging evidence shows that the cytosolic DNA sensor cyclic GMP-AMP synthase is pivotal in delivering activation signals to STING via the second messenger and cyclic dinucleotide (CDN) 2′3′-cyclic-GMP-AMP.

• Previous concerns that some CDNs were mouse specific abated when 2′3′-cyclic-GMP-AMP was found to be a universal activator of polymorphic human STING genes.

• Incorporating DNA or CDNs in vaccines offers considerable potential to improve vaccine efficacy provided that STING-mediated regulation does not attenuate adjuvant effects.

• DNA and CDNs also offer considerable potential to develop ‘tolerogenic’ vaccines to treat autoimmune syndromes.

Notes