Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
Project description:To investigate whether metoprolol treatment could affect the transcriptome and translatome of killing supernatant cultured human monocytes
Project description:ATAC sequencing of primary human monocytes cultured at low and high density. Monocytes isolated from PBMCs of 3 healthy donors were cultured at low density (1 x 10^6 cells/mL) or at high density (1 x10^7 cells/mL) for 24hrs and harvested for ATAC sequencing. Protein expression of FcgR2b is higher on monocytes in high density conditions compared to low density conditions, where expression is negligble. This study provides information on genome-wide chromatin accessibility changes that occur in high density culture in order to study associations with FcgR2b expression.