Ag-bearing liposomes engrafted with peptides that interact with CD11c/CD18 induce potent Ag-specific and antitumor immunity

Abstract

Dendritic cells (DCs) play key role in eliciting antigen (Ag)-specific immune responses, and crucial to this is the uptake of Ag via surface receptors including the heterodimeric integrin CD11c/CD18. Here we report that CD11c/CD18-interacting peptides can be used as targeting moieties to deliver liposomal Ag to antigen presenting cells (APCs) and elicit Ag-specific and antitumor immunity. Two peptides of sequence related to human ICAM-4 and previously reported to bind CD11c/CD18, and a 12-mer cyclic peptide previously identified by phage display to bind CD11c/CD18, were produced synthetically, and tested for their ability to target liposomal Ag. The three peptides were designed to contain a shorter spacer to reduce steric hindrance, and a His-tag to enable engraftment onto liposomes incorporated with chelator lipid. Our results show that the three peptides, denoted as p17, p18 and p30, promote strong binding of liposomes to CD11c+ and CD11b+ cells in vitro and in vivo. Vaccination of mice with Ag-bearing liposomes engrafted with the peptides, particularly p18 and p30, induced Ag-specific T cell priming and antibody production. Importantly, the vaccination of C57BL/6 mice with syngeneic B16-OVA-derived plasma membrane vesicles (PMVs) engrafted with p18 and p30 peptide showed dramatic antitumor responses, inhibiting tumor growth/metastasis in both the lung and subcutaneous tumor models, with a high proportion of the mice apparently being "cured" of their tumors. The engraftment of p18 and p30 peptides onto liposomes and PMVs, thus provides an effective means to target Ags to DCs in vivo, for the development of effective cancer vaccines and immunotherapies.