Modulating the activity of tumor-infiltrating dendritic cells (TiDCs) provides opportunities for novel cancer interventions. In this study, we report on the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (IT) delivery. We exploited this property to deliver mRNA encoding the co-stimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLNs). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We showed in various mouse cancer models that IT delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we showed that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such we provide a platform and a mechanistic rationale for the clinical testing of IT administration of TriMix mRNA.
- Received July 12, 2015.
- Revision received October 5, 2015.
- Accepted October 23, 2015.
- Copyright © 2015, American Association for Cancer Research.