Exploring the potential suppressive effects of breast and pancreatic tumors on generation and maturation of conventional dendritic cells (cDCs), Meyer et al. used mouse models with confirmatory human tissue analysis to show that tumor-induced expression of granulocyte colony-stimulating factor (GCSF), by downregulating the transcription factor IRF8 in cDC precursors, decreased cDC1s, the key generators of anti-tumor CD8+ T-cell responses. Antibody blockade of GCSF together with FLT3 ligand restored circulating and intratumoral cDC1 numbers.
Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141(+) DCs and mouse CD103(+) DCs, supports anti-tumor immunity by stimulating CD8(+) T-cell responses. Here, to understand how cDC1 development changes during tumor progression, we investigated cDC bone marrow progenitors. We found localized breast and pancreatic cancers induce systemic decreases in cDC1s and their progenitors. Mechanistically, tumor-produced granulocyte-stimulating factor downregulates interferon regulatory factor-8 in cDC progenitors, and thus results in reduced cDC1 development. Tumor-induced reductions in cDC1 development impair anti-tumor CD8(+) T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development.
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. (3) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. (4) Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. (5) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. (7) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. (8) Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. (9) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. (10) Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. (11) Department of Surgery, University of Rochester Medical Center, Rochester, NY, 14642, USA. (12) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA. (13) Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. (14) Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. John Cochran St. Louis Veterans Administration Hospital, St. Louis, MO, 63106, USA. (15) Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu.
