Ex vivo activation of dendritic cells via coacervate-mediated exogenous tumor cell lysate delivery

Abstract

For the successful development of various cellular products in cancer immunotherapy, an effective ex vivo priming technique for immune cells is often required. Among a variety of immunomodulatory substances, tumor cell lysates (TCLs) have been considered a robust immune activator with high adjuvanticity and tumor antigen population. Therefore, the present study suggests a novel ex vivo dendritic cell (DC) priming technique that utilizes (1) squaric acid (SqA)-mediated oxidation of source tumor cells to obtain antigenic TCLs with an increased immunogenic potential and (2) a coacervate (Coa) colloidal complex as an exogenous TCL carrier. Elevated oxidation by SqA-treated source tumor cells resulted in an increased immunogenic potential, indicated by a high level of damage-associated molecular pattern molecules in TCLs that could sufficiently stimulate DCs. Moreover, to effectively deliver these exogenous immunomodulating TCL DCs, Coa (i.e., a colloidal micro-carrier using cationic mPEGylated poly(ethylene arginyl aspartate diglyceride) and anionic heparin) was utilized for the sustained release of cargo TCLs and for preserving their bioactivity. Coa-mediated ex vivo delivery of SqA-treated TCLs (SqA-TCL-Coa) effectively promoted DC maturation through the enhanced uptake of antigens into target DCs, increased expression of DC activation markers, facilitated secretion of pro-inflammatory cytokines from activated DCs, and improved major histocompatibility complex-I dependent cross-presentation of a colorectal cancer specific antigen. Therefore, based on antigenic and adjuvant behaviors, our Coa-mediated exogenous delivery of SqA-TCL could be a promising application as a facile ex vivo DC priming strategy for further cell-based cancer immunotherapies.