Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Macrophages (M Phi) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MEDs that promote tumor immunosuppression will provide therapeutic benefit. PI3K gamma has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an M Phi Syk-PI3K axis drives polarization of immunosuppressive M Phi s that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3K gamma in M Phi s promotes a proinflammatory M Phi phenotype, restores CD8(+) T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow-derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-kappa B motif in Syk(MC-KO) BMDMs, thus stimulating immunostimulatory transcriptional programming in MEN to suppress tumor growth. Finally, we have developed in silico the first-in-class dual Syk/ PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.