Ferris et al. showed that GM-CSF-derived DCs (GMDCs) and Flt3L-derived cDC1s, but not cDC2s, cross-presented cell-associated antigens to CD8+ T cells in vitro. In contrast, in Irf8 +32-/- mice, which lack host cDC1s and are unresponsive to subcutaneous (s.c.) immunogenic fibrosarcomas, intratumoral (i.t.), but not intravenous (i.v.) injection of in vitro-generated cDC1s, but not GMDCs or cDC2s, induced rejection of the injected and uninjected contralateral s.c. tumors. The i.t.-injected cDC1s migrated to tumor-dLNs and stimulated tumor-specific CD4+ T and CD8+ T cells to induce primary and recall tumor rejection. Ex vivo antigen loading of cDC1s was not required.
Contributed by Paula Hochman
ABSTRACT: As a cell-based cancer vaccine, dendritic cells (DCs), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDCs), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1s) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared anti-tumor responses induced by GMDCs and cDC1 in Irf8 +32-/- mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8+ T cells in vitro. However, injection of GMDCs into tumors in Irf8 +32-/- mice did not induce anti-tumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 +32-/- mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce anti-tumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for anti-tumor therapy.