GSE144507 Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression and resistance to immune checkpoint blockade

Contributors : Samir Devalaraja ; Tsun K To ; Ian W Folkert ; Ramakrishnan Natesan ; Zahidul Alam ; Minghong Li ; Yuma Tada ; Konstantin Budagyan ; Mai Dang ; Li Zhai ; Graham P Lobel ; Gabrielle E Ciotti ; T K Eisinger-Mathason ; Irfan A Asangani ; Kristy Weber ; M C Simon ; Malay HaldarSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe 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 t...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research