Abstract
Abstract Tumors must evade immune-surveillance in order to progress. To this end, tumor-induced inflammation expands immune-suppressive immature granulocytes and monocytes, while limiting the functions of immune-stimulatory conventional dendritic cells (cDCs). cDC1s, a cDC subset, activate CD8+ T cells through antigen cross presentation and are marked by CD141 in humans and CD103 or CD8α in mice. cDC1s support anti-tumor CD8+ T cell responses, but cDC1 numbers are limited within the tumor environment. To understand how cDC1s are restricted in the tumor, we interrogated their development in the bone marrow (BM). We found the program responsible for the expansion of immature granulocytes and monocytes from progenitors in the BM is simultaneously suppressing the generation of cDC1s, decreasing the systemic numbers of cDC1s in breast and pancreatic cancer patients. We found that tumor-induced granulocyte stimulating factor (GCSF) mediates the down-regulation of the transcription factor IFN regulatory factor 8 (IRF8) in BM progenitors. IRF8 loss reprograms the BM progenitors, reducing their potential to develop into cDC1s. We demonstration, independent of monocyte and granulocyte expansion, that tumor-induced loss of cDC1s reduces the systemic ability to mount anti-tumor CD8+ T cell responses. Further, systemic decreases in cDC1s in breast cancer patients correlate with reduced response to chemotherapy. These data suggest a new mechanism of immune-escape whereby tumors down-regulate cDC1 differentiation from BM progenitors to impair anti-tumor CD8+ T cell immunity. These data beg the question; are some patients unresponsive to immunotherapy because of tumor-induced impairments in dendritic cell development? Citation Format: DeNardo DG. Do tumors overcome immune surveillance by blocking dendritic cell development [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-2.
Published Version
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