Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+ conventional dendritic cells

Abstract

Abstract Type 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, yet the efficacy of immunotherapy utilizingthis population is understudied. We used in vitro-generated CD103+cDC1s in vaccination strategies to test their ability to control melanoma and osteosarcoma tumors. In vitro-generated CD103+cDC1s produced cDC1-associated factors such as IL-12p70 and CXCL10, and demonstrated antigen cross-presentation activity upon stimulation with the Toll-like receptor 3 (TLR3) agonist polyinosinic:polycytidylic acid (poly I:C). In vitro-generated CD103+cDC1s also migrated to tumor-draining lymph nodes (TdLNs) following poly I:C treatment and intratumoral (i.t.) delivery. Vaccination with poly I:C-activated and tumor antigen-loaded CD103+cDC1s enhanced tumor infiltration of tumor antigen-specific and IFN-g+CD8+ T cells, and suppressed melanoma and osteosarcoma growth. CD103+cDC1s showed superior anti-tumor efficacy compared to vaccination with monocyte-derived DCs (MoDCs), and led to complete regression of 100% of osteosarcoma tumors in combination with CTLA-4 antibody-mediated checkpoint blockade. In addition, CD103+cDC1s effectively protected mice from pulmonary melanoma and osteosarcoma metastases. Our data indicate an in vitro-generated CD103+cDC1 vaccine elicits systemic and long-lasting tumor-specific T cell-mediated cytotoxicity, which restrains primary and metastatic tumor growth. The CD103+cDC1 vaccine was superior to MoDCs and enhanced response to immune checkpoint blockade. These results indicate the potential for new immunotherapies based on use of cDC1s alone or in combination with checkpoint blockade.