Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential.

The human dendritic cell (DC) family has recently been expanded by CD1cCD14CD163 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 CD1cCD14 DC frequencies correlate with reduced survival. We demonstrate conversion of CD5CD1cCD14 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 CD1cCD14 DCs and provides insights into the importance and modulation of CD14 DC3s in anti-tumor immune responses.