Discovery of highly immunogenic spleen-resident FCGR3CD103 cDC1s differentiated by IL-33-primed ST2 basophils.

Recombinant interleukin-33 (IL-33) inhibits tumor growth, but the detailed immunological mechanism is still unknown. IL-33-mediated tumor suppression did not occur in Batf3 mice, indicating that conventional type 1 dendritic cells (cDC1s) play a key role in IL-33-mediated antitumor immunity. A population of CD103 cDC1s, which were barely detectable in the spleens of normal mice, increased significantly in the spleens of IL-33-treated mice. The newly emerged splenic CD103 cDC1s were distinct from conventional splenic cDC1s based on their spleen residency, robust effector T-cell priming ability, and surface expression of FCGR3. DCs and DC precursors did not express Suppressor of Tumorigenicity 2 (ST2). However, recombinant IL-33 induced spleen-resident FCGR3CD103 cDC1s, which were found to be differentiated from DC precursors by bystander ST2 immune cells. Through immune cell fractionation and depletion assays, we found that IL-33-primed ST2 basophils play a crucial role in the development of FCGR3CD103 cDC1s by secreting IL-33-driven extrinsic factors. Recombinant GM-CSF also induced the population of CD103 cDC1s, but the population neither expressed FCGR3 nor induced any discernable antitumor immunity. The population of FCGR3CD103 cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs (FL-BMDCs) when IL-33 was added in a pre-DC stage of culture. FL-BMDCs generated in the presence of IL-33 (FL-33-DCs) offered more potent tumor immunotherapy than control Flt3L-BMDCs (FL-DCs). Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors. Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.