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

Autor:	Joshi S; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California. shjoshi@ucsd.edu durden@signalrx.com., Liu KX; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California., Zulcic M; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California., Singh AR; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California., Skola D; UCSD School of Medicine, University of California, San Diego, San Diego, California., Glass CK; UCSD School of Medicine, University of California, San Diego, San Diego, California., Sanders PD; Moores Cancer Center, Department of Radiation Medicine and Applied Sciences, University of California, San Diego, San Diego, California., Sharabi AB; Moores Cancer Center, Department of Radiation Medicine and Applied Sciences, University of California, San Diego, San Diego, California., Pham TV; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California.; Office of Cancer Genomics, University of California, San Diego, San Diego, California., Tamayo P; Office of Cancer Genomics, University of California, San Diego, San Diego, California., Shiang D; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California., Dinh HQ; La Jolla Institute of Allergy and Immunology, La Jolla, California., Hedrick CC; La Jolla Institute of Allergy and Immunology, La Jolla, California., Morales GA; SignalRx Pharmaceuticals, Omaha, Nebraska., Garlich JR; SignalRx Pharmaceuticals, Omaha, Nebraska., Durden DL; UCSD Department of Pediatrics, University of California, San Diego, San Diego, California. shjoshi@ucsd.edu durden@signalrx.com.; SignalRx Pharmaceuticals, Omaha, Nebraska.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2020 Mar; Vol. 19 (3), pp. 755-764. Date of Electronic Publication: 2020 Jan 23.
DOI:	10.1158/1535-7163.MCT-19-0947
Abstrakt:	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 Syk MC-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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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