Using syngeneic tumor models, Joshi et al. show that Syk kinase expression in macrophages promotes tumor growth and metastasis via immunosuppressive macrophage differentiation and inhibition of infiltration and activation of CD8+ T cells. Syk kinase regulates immunosuppressive macrophage gene expression by stabilization of HIF1α and HIF2α, similar to PI3Kγ. A dual Syk and PI3Kγ inhibitor, designed using a novel, structure-based computational method, further suppressed tumor growth, increased CD8+ T cell infiltration and cytotoxicity, and reduced immunosuppressive macrophage differentiation.
Contributed by Shishir Pant
ABSTRACT: Macrophages (MPhi) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MPhis that promote tumor immunosuppression will provide therapeutic benefit. PI3Kgamma has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MPhis which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kgamma in MPhis promotes a pro-inflammatory MPhiphenotype, 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 (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-kappaB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MPhis 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.
Author Info: (1) Pediatrics, Moores Cancer Center, University of California San Diego shjoshi@ucsd.edu. (2) Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center. (3) Pediatrics, Mo
Author Info: (1) Pediatrics, Moores Cancer Center, University of California San Diego shjoshi@ucsd.edu. (2) Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center. (3) Pediatrics, Moores Cancer Center, University of California San Diego. (4) Pediatrics, Moores Cancer Center, University of California San Diego. (5) Division of Biological Sciences, University of California, San Diego. (6) Division of Biological Sciences, University of California, San Diego. (7) Department of Radiation Medicine and Applied Sciences, University of California - San Diego School of Medicine. (8) Radiation Medicine and Applied Sciences, University of California, San Diego. (9) Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center. (10) UCSD Moores Cancer Center, University of California, San Diego. (11) Pediatrics, Moores Cancer Center, University of California San Diego. (12) Inflammation Biology, La Jolla Institute for Immunology. (13) Inflammation Biology, La Jolla Institute. (14) Hematology and Oncology, SignalRx Pharmaceuticals. (15) Hematology and Oncology, SignalRx Pharmaceuticals. (16) Hematology and Oncology, SignalRx Pharmaceuticals.
