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

• Published in: Nature communications Vol. 9; no. 1; pp. 1250 - 19
• Main Authors: Meyer, Melissa A., Baer, John M., Knolhoff, Brett L., Nywening, Timothy M., Panni, Roheena Z., Su, Xinming, Weilbaecher, Katherine N., Hawkins, William G., Ma, Cynthia, Fields, Ryan C., Linehan, David C., Challen, Grant A., Faccio, Roberta, Aft, Rebecca L., DeNardo, David G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/105; 13/106; 13/109; 13/21; 13/31; 13/51; 14/63; 38; 38/61; 45/88; 631/250; 631/250/232/2059; 631/67/580; 64/60; Animals; Antigens, CD - metabolism; Antigens, Surface - metabolism; Antineoplastic Agents - pharmacology; Bone marrow; Bone Marrow Cells - metabolism; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; CD103 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Female; Humanities and Social Sciences; Humans; Immunity; Immunologic Surveillance; Immunosuppression; Immunosurveillance; Immunotherapy; Integrin alpha Chains - metabolism; Interferon; Interferon regulatory factor; Interferon Regulatory Factors - metabolism; Leukocytes (granulocytic); Lymphocytes T; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Myeloid cells; Myelopoiesis; Oligonucleotide Array Sequence Analysis; Osteoprogenitor cells; Pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Rodents; Science; Science (multidisciplinary); Stem Cells - metabolism; Surveillance; T cell receptors; T-Lymphocytes - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03600-6

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. Tumors escape the immune system through many mechanisms. Here the authors show that certain tumors inhibit anti-tumor immunity by stopping the production of conventional dendritic cells (cDCs) in the bone marrow, therefore depleting the pool of cDCs available to present antigen to CD8 + T cells.