A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy.

Abstract

The in vivo therapeutic efficacy of DC-based cancer vaccines is limited by suboptimal DC maturation protocols. Although delivery of TLR adjuvants systemically boosts DC-based cancer vaccine efficacy, it could also increase toxicity. Here, we have engineered a drug-inducible, composite activation receptor for DCs (referred to herein as DC-CAR) comprising the TLR adaptor MyD88, the CD40 cytoplasmic region, and 2 ligand-binding FKBP12 domains. Administration of a lipid-permeant dimerizing ligand (AP1903) induced oligomerization and activation of this fusion protein, which we termed iMyD88/CD40. AP1903 administration to vaccinated mice enabled prolonged and targeted activation of iMyD88/CD40-modified DCs. Compared with conventionally matured DCs, AP1903-activated iMyD88/CD40-DCs had increased activation of proinflammatory MAPKs. AP1903-activated iMyD88/CD40-transduced human or mouse DCs also produced higher levels of Th1 cytokines, showed improved migration in vivo, and enhanced both antigen-specific CD8+ T cell responses and innate NK cell responses. Furthermore, treatment with AP1903 in vaccinated mice led to robust antitumor immunity against preestablished E.G7-OVA lymphomas and aggressive B16.F10 tumors. Thus, the iMyD88/CD40 unified "switch" effectively and safely replaced exogenous adjuvant cocktails, allowing remote and sustained DC activation in vivo. DC "licensing" through iMyD88/CD40 may represent a mechanism by which to exploit the natural synergy between the TLR and CD40 signaling pathways in DCs using a single small molecule drug and could augment the efficacy of antitumor DC-based vaccines.

• Authors: Priyadharshini Narayanan, Natalia Lapteva, Mamatha Seethammagari, Jonathan M Levitt, Kevin M Slawin, David M Spencer
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 4 Pg. 1524-34 (Apr 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 21383499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• CD40 Antigens
• Cancer Vaccines
• MYD88 protein, human
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Organic Chemicals
• Toll-Like Receptors
• Tacrolimus Binding Protein 1A
• AP 1903 reagent

Topics

• Adjuvants, Immunologic (administration & dosage)
• Animals
• CD40 Antigens (administration & dosage, genetics, immunology)
• Cancer Vaccines (administration & dosage, genetics, immunology)
• Dendritic Cells (immunology)
• Drug Synergism
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (administration & dosage, genetics, immunology)
• NF-kappa B (metabolism)
• Neoplasms, Experimental (immunology, therapy)
• Organic Chemicals (administration & dosage)
• Protein Engineering
• Tacrolimus Binding Protein 1A (genetics, immunology)
• Toll-Like Receptors (immunology)