Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance

Melissa A. Meyer, John M. Baer, Brett L. Knolhoff, Timothy M. Nywening, Roheena Z. Panni, Xinming Su, Katherine N. Weilbaecher, William G. Hawkins, Cynthia Ma, Ryan C. Fields, David C. Linehan, Grant A. Challen, Roberta Faccio, Rebecca L. Aft and David G. DeNardo ()
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Melissa A. Meyer: Washington University School of Medicine
John M. Baer: Washington University School of Medicine
Brett L. Knolhoff: Washington University School of Medicine
Timothy M. Nywening: Washington University School of Medicine
Roheena Z. Panni: Washington University School of Medicine
Xinming Su: Washington University School of Medicine
Katherine N. Weilbaecher: Washington University School of Medicine
William G. Hawkins: Washington University School of Medicine
Cynthia Ma: Washington University School of Medicine
Ryan C. Fields: Washington University School of Medicine
David C. Linehan: University of Rochester Medical Center
Grant A. Challen: Washington University School of Medicine
Roberta Faccio: Washington University School of Medicine
Rebecca L. Aft: Washington University School of Medicine
David G. DeNardo: Washington University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03600-6

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