Vaccination against neoantigens induced in cross-priming cDC1 in vivo

Area of Science:

• Immunology
• Cancer Biology
• Drug Delivery

Background:

• Conventional type 1 dendritic cells (cDC1) are crucial for anti-tumor immunity but are infrequent, limiting their therapeutic use.
• Previous methods using TLR9-targeted siRNA faced challenges due to TLR9 expression in immunosuppressive myeloid cells.
• Targeting neoantigens via siRNA delivery to dendritic cells is a promising cancer vaccine strategy.

Purpose of the Study:

• To develop a novel antibody-based platform for targeted delivery of siRNA to cDC1.
• To investigate the efficacy of co-delivering TAP siRNA and a DC maturation agent to cDC1.
• To enhance cancer immunotherapy by manipulating cDC1 function in vivo.

Main Methods:

• A modular multivalent antibody platform was engineered to target Clec9a on cDC1.
• The platform delivered short interfering RNA (siRNA) targeting the Transporter Associated with Antigen Processing (TAP).
• The platform was adapted to co-deliver TAP siRNA and a CpG oligonucleotide for DC maturation.

Main Results:

• The antibody platform achieved selective and sustained TAP downregulation in cDC1.
• Targeting cDC1 with TAP siRNA via the antibody platform inhibited tumor growth more effectively than CpG-targeted siRNA.
• Co-delivery of TAP siRNA and CpG oligonucleotide to cDC1 proved more effective than combining Clec9a targeting with CD40 antibody.

Conclusions:

• A broadly applicable antibody-based platform can effectively target and manipulate cDC1 function in vivo.
• This platform enables the delivery of multiple biological agents to specific immune cells for enhanced immunotherapy.
• The study provides a novel strategy to potentiate immune therapy and study cell biology in vivo.