Becker et al. showed that patients with NSCLC had increased blood levels of CD1c+CD14+ DC3s expressing an immunosuppressive phenotype and reduced T cell stimulatory activity. Patients with melanoma receiving CD1c+ DC vaccines with higher CD1c+CD14+ DC levels had shorter PFS. Transcriptomic analyses showed a stronger relationship between CD1c+CD14+ cells and cDC2s than CD14+ monocytes. cDC2s, but not monocytes, were induced by tumor-derived factors to differentiate into CD1c+CD14+ cells in vitro. M-CSF and IL-6 were primary tumor drivers of CD14- to CD14+ DC conversion, and IL-6R and CSF1R inhibition blocked tumor-induced CD14+ cDC2 differentiation and enhanced T cell activation.
Contributed by Paula Hochma
ABSTRACT: 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.
Author Info: (1) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (2) Department of Tumor Imm
Author Info: (1) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (2) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (3) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (4) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (5) Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (6) Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands. (7) Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands. (8) Department of Pulmonology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (9) Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (10) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Institute for Chemical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. (11) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: jolanda.devries@radboudumc.nl.
