%0 Journal Article
%T Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential.
%A Becker AMD
%A Decker AH
%A Flórez-Grau G
%A Bakdash G
%A Röring RJ
%A Stelloo S
%A Vermeulen M
%A Piet B
%A Aarntzen EHJG
%A Verdoes M
%A de Vries IJM
%J Cell Rep Med
%V 5
%N 2
%D 2024 Feb 20
%M 38242119
%F 16.988
%R 10.1016/j.xcrm.2023.101386
%X The human dendritic cell (DC) family has recently been expanded by CD1c+CD14+CD163+ DCs, introduced as DC3s. DC3s are found in tumors and peripheral blood of cancer patients. Here, we report elevated frequencies of CD14+ cDC2s, which restore to normal frequencies after tumor resection, in non-small cell lung cancer patients. These CD14+ cDC2s phenotypically resemble DC3s and exhibit increased PD-L1, MERTK, IL-10, and IDO expression, consistent with inferior T cell activation ability compared with CD14- cDC2s. In melanoma patients undergoing CD1c+ DC vaccinations, increased CD1c+CD14+ DC frequencies correlate with reduced survival. We demonstrate conversion of CD5+/-CD1c+CD14- cDC2s to CD14+ cDC2s by tumor-associated factors, whereas monocytes failed to express CD1c under similar conditions. Targeted proteomics identified IL-6 and M-CSF as dominant drivers, and we show that IL-6R and CSF1R inhibition prevents tumor-induced CD14+ cDC2s. Together, this indicates cDC2s as direct pre-cursors of DC3-like CD1c+CD14+ DCs and provides insights into the importance and modulation of CD14+ DC3s in anti-tumor immune responses.