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

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.