Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103 conventional dendritic cells
ABSTRACT
BACKGROUND: Type 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, as well as potent T cell priming ability. Tissue-resident cDC1s (CD103 cDC1s in mice, CD141 cDC1s in humans) are linked with improved tumor control, yet the efficacy of immunotherapy using this population is understudied.
METHODS: We generated murine CD103 cDC1s in vitro and examined their expression of cDC1-related factors, antigen cross-presentation activity, and accumulation in tumor-draining lymph nodes (TdLNs). The antitumor efficacy of the in vitro-generated CD103 cDC1s was studied in murine melanoma and osteosarcoma models. We evaluated tumor responses on vaccination with CD103 cDC1s, compared these to vaccination with monocyte-derived DCs (MoDCs), tested CD103 cDC1 vaccination with checkpoint blockade, and examined the antimetastatic activity of CD103 cDC1s.
RESULTS: In vitro-generated CD103 cDC1s produced cDC1-associated factors such as interleukin-12p70 and CXCL10, and demonstrated antigen cross-presentation activity on stimulation with the toll-like receptor 3 agonist polyinosinic:polycytidylic acid (poly I:C). In vitro-generated CD103 cDC1s also migrated to TdLNs following poly I:C treatment and intratumoral delivery. Vaccination with poly I:C-activated and tumor antigen-loaded CD103 cDC1s enhanced tumor infiltration of tumor antigen-specific and interferon-γ CD8 T cells, and suppressed melanoma and osteosarcoma growth. CD103 cDC1s showed superior antitumor efficacy compared with MoDC vaccination, and led to complete regression of 100% of osteosarcoma tumors in combination with CTLA-4 antibody-mediated checkpoint blockade. In vitro-generated CD103 cDC1s effectively protected mice from pulmonary melanoma and osteosarcoma metastases.
CONCLUSIONS: 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.