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.
Highlights
Tumors employ multiple mechanisms to evade immune surveillance
We analyzed the following conventional dendritic cells (cDCs) progenitors: macrophagedendritic cell progenitors (MDPs), which retain monocyte/macrophage potential; common dendritic cell progenitors (CDPs), which retain plasmacytoid DC potential; and pre-DCs, which are committed to the cDC lineage
These data suggest the defect in bone marrow (BM) progenitors is strongest and most consistent after progenitors start to commit to the cDC lineage
Summary
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. CD103+ DCs, supports anti-tumor immunity by stimulating CD8+ T-cell responses. Tumor-induced reductions in cDC1 development impair anti-tumor CD8+ T-cell responses and correlate with poor patient outcomes. Conventional dendritic cells (cDCs) support anti-tumor adaptive immunity by stimulating T cells, but cDCs often fail to accumulate in the tumor microenvironment[1,2]. Solid tumors interfere with anti-tumor immune responses by stimulating immature granulocyte and monocyte production from bone marrow (BM) progenitors. Expanded myeloid cells are recruited to tumors where they can maintain an immature phenotype or differentiate into tumor-associated macrophages All of these populations can suppress anti-tumor CD8+ T cells as well as promote tumor progression through support of angiogenesis and metastasis[7,8,9,10]. The cDC1s are marked by CD141 in humans and encompass both migratory
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