PLX145330

GSE123154: SF2523: Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Macrophages (MQs) are key immune infiltrates in solid tumors and serve as major drivers behind tumor growth, immune suppression, and inhibition of adaptive immune responses in the tumor microenvironment (TME). Bromodomain and extraterminal (BET) protein, BRD4, which binds to acetylated lysine on histone tails has recently been reported to promote gene transcription of pro-inflammatory cytokines, but has rarely been explored for its role in IL4-driven macrophage transcriptional programming and macrophage-mediated immunosuppression in the TME. Herein, we report that BET bromodomain inhibitor JQ1, blocks association of BRD4 with promoters of arginase and other IL4-driven macrophage genes, which promote immunosuppression in TME. Pharmacological inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous mice models; reduces infiltration of MDSCs; blocks polarization of immunosuppressive MQs; restores CD8+ T-cell activity and stimulates anti-tumor immune responses. Finally, our results suggest that BRD4 controls the immunosuppressive myeloid tumor microenvironment and provide opportunity to test BET inhibitors and dual PI3K/BRD4 inhibitors to treat cancers driven by the MQ-dependent immunosuppressive TME. SOURCE: Donald Durden (ddurden@ucsd.edu) - Moores Cancer Center, Room 5305 UCSD Moores Cancer Center