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

Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance.
Author Information (click to view)

Meyer MA, Baer JM, Knolhoff BL, Nywening TM, Panni RZ, Su X, Weilbaecher KN, Hawkins WG, Ma C, Fields RC, Linehan DC, Challen GA, Faccio R, Aft RL, DeNardo DG,


Meyer MA, Baer JM, Knolhoff BL, Nywening TM, Panni RZ, Su X, Weilbaecher KN, Hawkins WG, Ma C, Fields RC, Linehan DC, Challen GA, Faccio R, Aft RL, DeNardo DG, (click to view)

Meyer MA, Baer JM, Knolhoff BL, Nywening TM, Panni RZ, Su X, Weilbaecher KN, Hawkins WG, Ma C, Fields RC, Linehan DC, Challen GA, Faccio R, Aft RL, DeNardo DG,

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Nature communications 2018 03 289(1) 1250 doi 10.1038/s41467-018-03600-6

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 CD141DCs and mouse CD103DCs, supports anti-tumor immunity by stimulating CD8T-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 CD8T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development.

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