In vitro, Zhou et al. generated CD103+ DCs from mouse bone marrow that phenotypically resembled type 1 conventional DCs. Compared to monocyte-derived DCs typically used in DC vaccination trials, activated and antigen-loaded CD103+ DCs injected into melanoma tumors improved draining lymph node migration, CD8+ T cell responses, and tumor control. In an osteosarcoma model, vaccination with CD103+ DCs bearing tumor lysate synergized with anti-CTLA-4 therapy to regress 100% of tumors and generate immunological memory. In both models, intravenously administered CD103+ DCs effectively reduced lung metastases.
Contributed by Alex Najibi
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-gamma(+) 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.
Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (3) Immunolo
Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (3) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (4) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (5) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (6) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (7) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (8) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (9) Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA swatowic@mdanderson.org.
