TY - JOUR
T1 - Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance
AU - Meyer, Melissa A.
AU - Baer, John M.
AU - Knolhoff, Brett L.
AU - Nywening, Timothy M.
AU - Panni, Roheena Z.
AU - Su, Xinming
AU - Weilbaecher, Katherine N.
AU - Hawkins, William G.
AU - Ma, Cynthia
AU - Fields, Ryan C.
AU - Linehan, David C.
AU - Challen, Grant A.
AU - Faccio, Roberta
AU - Aft, Rebecca L.
AU - Denardo, David G.
N1 - Funding Information:
We would like to thank T. Murphy and K. Murphy (Washington University in St. Louis, USA) for the MSCV Irf8 T2a Thy1.1 and MSCV empty vector T2a Thy1.1 control as well as intellectual input. This work was supported by funding awarded to D.G.D. from the Department of Defense (W81XWH-15-1-0385) and the National Cancer Institute (P50 CA196510, R01 CA177670, R01 CA203890). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analyses. The Center is partially supported by NCI Cancer Center Support (P30 CA91842) to the Siteman Cancer Center and by ICTS/CTSA (UL1RR024992) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044526055&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03600-6
DO - 10.1038/s41467-018-03600-6
M3 - Article
C2 - 29593283
AN - SCOPUS:85044526055
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1250
ER -