Induction of antigen-presenting monocyte-derived dendritic cells by nanoparticles inhibits metastasis and relieves immunosuppression in the metastatic niche

Myeloid immune cells play a major role in establishing a suitable microenvironment for metastatic tumor cells. Dysregulated myeloid cells suppress antigen-presentation pathways and effector T cell responses at distal organs, and reprogramming these cells may enhance anti-tumor cytotoxicity. Targeting myeloid cells with poly(lactide-co-glycolide) nanoparticles, which possess intrinsic immunomodulatory properties, can promote monocyte maturation to inhibit metastasis. Intravenously delivered nanoparticles made with polyvinyl alcohol, but not other surfactants, reduce the accumulation of neutrophils at the metastatic niche and induce the differentiation of monocytes into antigen-presenting monocyte-derived dendritic cells. The internalization of nanoparticles was linked to the upregulation of gene expression programs in monocyte-derived dendritic cells associated with antigen presentation and T cell stimulation, and ligand-receptor network modeling supports increased activation of Th1 cells by these monocyte-derived dendritic cells. Nanoparticle administration increased the proportion of CD4 cells with Th1 and Th17 phenotypes and did not inhibit metastasis in mice where monocytes or T cells were depleted, indicating that interactions between monocyte-derived dendritic cells and T cells are essential to the mechanism of action. Collectively, our findings demonstrate that nanoparticles can reprogram circulating monocytes into monocyte-derived dendritic cells to modulate the metastatic niche and enhance antigen presentation to stimulate intrinsic T cell responses. Overall design: Lungs were isolated from female BALB/c 4T1-tumor bearing mice at D14 post-inoculation (inoculated with 50 uL of 2e6 4T1 cells/mL). Mice were treated with saline (control) or 1mg of NPs every three days starting at D1 post-inocluation (D1, 4, 7, 10, 13 NP treatments). Cells were then prepared for flow-assisted cell sorting by staining with AF488-CD45 and sorted into CD45+NP+, CD45+NP-, and CD45- populations on the Bigfoot Cell Sorter. Sorted samples were fixed with the 10x Chromium Next GEM Single Cell Fixed RNA Sample Preparation Kit following manufacturer instructions. Fixed samples were submitted to the University of Michigan Advanced Genomics Core for library preparation with the 10x Single Cell Fixed RNA Hybridization & Library Kit and Single Cell Fixed RNA Mouse Transcriptome Probe Kit following manufacturer guidelines for the 10x Single Cell Gene Expression Flex platform. Samples were sequenced on the NovaSeq X 10B flow cells (300 cycle) at a depth of approximately 25,000 reads per cell.