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Molecular Cancer Therapeutics
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Research Article

Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression

Shweta Joshi, Kevin X Liu, Muamera Zulcic, Alok R. Singh, Dylan Skola, Christopher K. Glass, P. Dominick Sanders, Andrew B Sharabi, Timothy V. Pham, Pablo Tamayo, Daniel Shiang, Huy Q. Dinh, Catherine C. Hedrick, Guillermo A. Morales, Joseph R. Garlich and Donald L. Durden
Shweta Joshi
1Pediatrics, Moores Cancer Center, University of California San Diego
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  • For correspondence: shjoshi@ucsd.edu
Kevin X Liu
2Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center
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Muamera Zulcic
1Pediatrics, Moores Cancer Center, University of California San Diego
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Alok R. Singh
1Pediatrics, Moores Cancer Center, University of California San Diego
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Dylan Skola
3Division of Biological Sciences, University of California, San Diego
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Christopher K. Glass
3Division of Biological Sciences, University of California, San Diego
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P. Dominick Sanders
4Department of Radiation Medicine and Applied Sciences, University of California - San Diego School of Medicine
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Andrew B Sharabi
5Radiation Medicine and Applied Sciences, University of California, San Diego
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Timothy V. Pham
6Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center
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Pablo Tamayo
7UCSD Moores Cancer Center, University of California, San Diego
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Daniel Shiang
1Pediatrics, Moores Cancer Center, University of California San Diego
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Huy Q. Dinh
8Inflammation Biology, La Jolla Institute for Immunology
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Catherine C. Hedrick
9Inflammation Biology, La Jolla Institute
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Guillermo A. Morales
10Hematology and Oncology, SignalRx Pharmaceuticals
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Joseph R. Garlich
10Hematology and Oncology, SignalRx Pharmaceuticals
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Donald L. Durden
10Hematology and Oncology, SignalRx Pharmaceuticals
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DOI: 10.1158/1535-7163.MCT-19-0947
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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 a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, 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-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.

  • Received October 2, 2019.
  • Revision received December 5, 2019.
  • Accepted January 9, 2020.
  • Copyright ©2020, American Association for Cancer Research.
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This OnlineFirst version was published on January 23, 2020
doi: 10.1158/1535-7163.MCT-19-0947

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Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression
Shweta Joshi, Kevin X Liu, Muamera Zulcic, Alok R. Singh, Dylan Skola, Christopher K. Glass, P. Dominick Sanders, Andrew B Sharabi, Timothy V. Pham, Pablo Tamayo, Daniel Shiang, Huy Q. Dinh, Catherine C. Hedrick, Guillermo A. Morales, Joseph R. Garlich and Donald L. Durden
Mol Cancer Ther January 23 2020 DOI: 10.1158/1535-7163.MCT-19-0947

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Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression
Shweta Joshi, Kevin X Liu, Muamera Zulcic, Alok R. Singh, Dylan Skola, Christopher K. Glass, P. Dominick Sanders, Andrew B Sharabi, Timothy V. Pham, Pablo Tamayo, Daniel Shiang, Huy Q. Dinh, Catherine C. Hedrick, Guillermo A. Morales, Joseph R. Garlich and Donald L. Durden
Mol Cancer Ther January 23 2020 DOI: 10.1158/1535-7163.MCT-19-0947
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Molecular Cancer Therapeutics
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