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

Mol Cancer Ther. 2020 Mar;19(3):755-764. doi: 10.1158/1535-7163.MCT-19-0947. Epub 2020 Jan 23.

Abstract

Macrophages (MΦ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MΦ Syk-PI3K axis drives polarization of immunosuppressive MΦs that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3Kγ in MΦs promotes a proinflammatory MΦ 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-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / enzymology
  • Carcinoma, Lewis Lung / immunology*
  • Carcinoma, Lewis Lung / pathology
  • Cell Proliferation
  • Class Ib Phosphatidylinositol 3-Kinase / chemistry*
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / pathology
  • Cytokines / metabolism
  • Humans
  • Immune Tolerance
  • Immunosuppression
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / enzymology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology*
  • Signal Transduction
  • Syk Kinase / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Cytokines
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • SYK protein, human
  • Syk Kinase