Friday, June 3, 2016

Tumor protein encoding [negatively charged] RNA-nanoparticles induced robust anti-tumor response

In earlier studies for in vivo delivery of RNA/DNA nucleic acids into antigen-presenting cells scientists have used positively charged [cationic] nanoparticles. However, such particles were mostly trapped within lungs rather than lymphoid tissues where most antigen-presenting cells, such as dendrtic cells, reside. Surprisingly, here the authors showed that negatively charged RNA-nanoparticles selectively accumulated in spleen within antigen-presenting cells after in vivo injection.

Strangely, accumulation of RNA-nanoparticles were reduced when mice were depleted of conventional DCs (cDCs) after diphtheria toxin injection (CD11-DRT BM chimera mice), even though these mice retain both plasmacytoid DCs (pDCs) and macrophages which can themselves capture RNA-nanoparticles.

RNA-nanoparticle injection was associated with rapid IFN-α secretion in a manner that depended on TLR7 expression.

In addition, RNA-nanoparticles induced robust priming of antigen-specific adaptive immune response.

More importantly, injection of tumor protein encoding RNA-nanoparticles delivered incredibly robust prophylactic and therapeutic anti-tumor effect (article has some preliminary  results from phase I study showing T cell priming in cancer patient after RNA-nanoparticle delivery).

In summary, the authors of this study believe that they found universal antigen delivery RNA-nanoparticle construct that induces robust adaptive immune response.

There is one thing that is puzzling about this study which the authors did not tried explain: in mice depletion of cDCs eliminated RNA-nanoparticle uptake and T cell priming. However, pDCs are not depleted in CD11c-DTR chimera mice and the data showed that pDCs are themselves could capture RNA-nanoparticles and are the main source of type I IFNs. So, the question then is why cDCs depletion has such disproportional effect?

David Usharauli

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