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

• DOI: 10.1016/j.xcrm.2023.101386
• Publication Date: 2024-01-18T15:37:25Z
• Authors: Anouk M.D. Becker; Annika H. Decker; Georgina Flórez-Grau; Ghaith Bakdash; Rutger J. Röring; Suzan Stelloo; Michiel Vermeulen; Berber Piet; Erik H.J.G. Aarntzen; Martijn Verdoes; I. Jolanda M. de ...
• Keywords: 0303 health sciences; Lung Neoplasms; Proteomics and Chromatin Biology; 610; Receptor Protein-Tyrosine Kinases; Dendritic Cells; Medical Biosciences - Radboud University Medical Center; Article; Monocytes; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Medical Imaging - Radboud University Medical Center; Receptors, Colony-Stimulating Factor; Humans; Internal Medicine - Radboud University Medical Center; Pulmonary Diseases - Radboud University Medical Center; Molecular Biology; Signal Transduction

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.