Engineering better immunotherapies via RNA interference.

The therapeutic potential of dendritic cell (DC) cancer vaccines has gained momentum in recent years. However, clinical data indicate that antitumor immune responses generally fail to translate into measurable tumor regression. This has been ascribed to a variety of tolerance mechanisms, one of which is the expression of immunosuppressive factors by DCs and T cells. With respect to cancer immunotherapies, these factors antagonise the ability to induce robust and sustained immunity required for tumor cell eradication. Gene silencing of immunosuppressive factors in either DCs or adoptive transferred T cells enhanced anti-tumor immune responses and significantly inhibited tumor growth. Therefore, engineered next generation of DC vaccines or adoptive T-cell therapy should include immunomodulatory siRNAs to release the "brakes" imposed by the immune system. Moreover, the combination of gene silencing, antigen targeting to DCs and cytoplasmic cargo delivery will improve clinical benefits.