Expression data from tumor-infiltrating macrophages.. Expression data from tumor-infiltrating macrophages.

The microenvironment has profound effect on macrophage phenotype. Here we examine the phenotype of macrophages infiltrating murine undifferentiated pleomorphic sarcomas. We used microarray to examine gene expression profile of tumor-associated macrophages in murine undifferentiated pleomorphic sarcomas. 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. Overall design: Undifferentiated pleomorphic sarcomas were generated by injecting adenoviral cre recombinase in genetically engineered mice where Trp53 deletion and Kras activation occurs in the presence of Cre recombinase. Tumors were subjected to enzymatic digestion to generate single cell suspension and macrophages (7AAD-CD45+B220-CD11C-F4/80+) isolated by FACsorting. Microarray was performed on isolated macrophages.