Monocytes outperform ex vivo generated dendritic cells as cellular vaccines to trigger cytotoxic T lymphocyte responses against cancer in pre-clinical models

Abstract

Abstract Conventional dendritic cell (DC) vaccines using ex vivo generated DC have been widely tested in clinical trials in the treatment of human cancers. These DC vaccines have often displayed limited efficacy despite a complex manufacturing process. Although the efficacy of DC vaccines is generally thought to depend on their antigen-presenting cell function, several lines of evidence suggest that, instead of directly presenting antigen (Ag) to naïve T cells, administered DC trigger cytotoxic T lymphocyte (CTL) responses in vivo mainly by transferring Ag to lymphoid-resident conventional DC (cDC). We tested here whether monocytes, known to transfer Ag to cDC in vivo, can be directly loaded with tumor Ag to trigger robust anti-tumor CTL responses. We found that IV administered monocytes loaded with protein or peptide Ag triggered stronger Ag-specific CTL responses than conventional adjuvant-based and DC vaccines. In several murine cancer models, including intra-cranial glioblastoma, we showed that monocyte vaccination suppressed tumor growth better than conventional adjuvant-based, GVAX and DC vaccines. Such anti-tumor activities could be further enhanced with immune checkpoint inhibition. Ag-loaded monocytes did not directly activate naïve CD8+T cells. Instead, they formed stable physical contacts with and transferred Ag to splenic CD8+cDC. This Ag transfer required the formation of connexin 43-containing gap junctions between monocytes and CD8+cDC. Our findings demonstrated that gap junctions are an efficient Ag transfer pathway in vivo between monocytes and splenic CD8+cDC and suggested that IV administered Ag-loaded monocytes may serve as a simple and efficacious cellular vaccine platform for the treatment of human cancers.