75P - Double-stranded RNA transfection induced anti-tumour effect mediated by dual RIG-I and TLR-3 immune pathways

Background

Cancer immunotherapy is dependent on immunostimulation to reorganise the tumour microenvironment (TME) and to increase anti-tumour effects of immune cells. There are currently many immunostimulants applicable to cancer therapy, such as antibodies, molecular drugs and PAMP activators. Choice of immunostimulant may be key, but method of delivery of treatment is equally as important as different routes may stimulate different immune pathways. Despite of the rapid development of nucleic acid drugs in recent years, the effect of nucleic acid on tumor immunity needs to be further investigated. Polyinosinic:polycytidylic acid (poly I:C) is a synthetic double-stranded RNA analog that shows promise as an adjuvant in cancer vaccines or immunotherapies. Poly I:C is known to interact with Toll-like receptor 3 (TLR3) when taken up by endocytosis, but when directly transfected into cells, poly I:C stimulates retinoic acid-inducible gene I (RIG-I) instead.

Methods

Poly I:C was used to mimic anti-tumour response after nucleic acid administration. Murine 4T1 mammary tumour-bearing BALB/c mice were treated with poly I:C by electroporation (EP) or syringe injection (SI) and monitored for tumour growth. To determine whether poly I:C-activated immune pathways differed between delivery modes, RIG-I and TLR3 pathway inhibitors were used to inhibit poly I:C-induced anti-tumour effect in 4T1 tumour model.

Results

Our results showed that poly I:C EP treatment induced stronger tumour suppression effect and tumour-specific adaptive immune response than via SI. And that this EP-treated anti-tumour effect could be suppressed by both RIG-I and TLR3 pathway inhibitors, but not in SI, suggesting that treatment of poly I:C via different delivery modes do activate different immune pathways.

Conclusions

We have demonstrated that poly I:C could induce different anti-tumour effects dependent on treatment delivery method. Our results suggest that the effects of nucleic acid drugs may vary depending on how they are administered.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Osaka University.

Funding

Osaka University.

Disclosure

All authors have declared no conflicts of interest.