Abstract 109: Myeloid Syk-PI3Kg-HIF axis inhibits anti-tumor adaptive immunity: In silico design of a “first in class” novel dual-Syk/PI3K inhibitor, SRX3207, to block the immunosuppressive tumor microenvironment
Authors: Joshi Shweta , Liu Kevin , Zulcic Muamera , Singh Alok , Pham Timothy , Glass Christopher K. , Sharabi Andrew , Morales Guillermo A. , Garlich Joseph R. , Durden Donald 
Published: August 2019

Introduction: Macrophages (MΘs) play important roles in the initiation and progression of solid tumors and in establishing an immunosuppressive tumor microenvironment (TME) that dampens effective anti-tumor immune responses in cancer. Hence, targeting signaling pathways in MΘs that promote tumor immunosuppression will provide therapeutic benefit. Syk kinase is a well-established cytoplasmic protein tyrosine kinase that has been extensively studied in adaptive immune responses, but its role in macrophage-mediated inflammatory responses and innate immune responses remains poorly understood. The role of PI3Kγ in tumor growth and immunosuppression has been recently established by our and other groups. Our current study examines whether targeting two crucial signaling entities, which promote macrophage-mediated anti-inflammatory responses viz. Syk kinase and PI3K, would maximally activate the anti-tumor immune response.

Methodology: 1) We generated myeloid-specific conditional Syk k/o mice to investigate if the deletion of Syk has any role in a) macrophage polarization in vitro and in vivo; b) tumor growth in various syngeneic mouse models including LLC, B16, CT26, and MC38 carcinoma; c) tumor immunosuppression including polarization of macrophages into immunosuppressive phenotype, infiltration of myeloid-derived suppressor cells, regulatory T cells; and d) infiltration and activation of CD8+T cells in the TME. 2) We used commercially available Syk inhibitor, R788, to study the role of Syk in the control of the aforementioned phenotypes. 3) We used computational chemistry methods to develop a novel chemotype, SRX3207, which inhibits both PI3K and Syk (with a single molecule) as a strategy for combinatorial activation of anti-cancer immunity.

Results: Our results suggest that macrophage, Syk, functions upstream of Rac2 GTPase and PI-3K to modulate integrin (αvβ3/αvβ5&α4β1)-mediated polarization of immunosuppressive macrophages and tumor growth in in vivo syngeneic tumor models. Genetic or pharmacological blockade of Syk in MΘs promotes a pro-inflammatory MΘ phenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Moreover, Syk-regulated immune response gene signature predicts survival in cancer patients. Novel dual-Syk/PI3K inhibitor, SRX3207, shows great efficacy in various syngeneic tumor models with no toxicity.

Conclusions: Our results validate the concept of combined Syk and PI3K inhibition as an effective approach to treat macrophage-driven, devastating cancers. This study will open new avenues to explore this chemotype in combination with other immuno-oncologic agents as the majority of cancer patients do not respond to single agent anti-PD1 or other checkpoint inhibitors currently in clinical use.

Citation Format: Shweta Joshi, Kevin Liu, Muamera Zulcic, Alok Singh, Timothy Pham, Christopher K. Glass, Andrew Sharabi, Guillermo A. Morales, Joseph R. Garlich, Donald Durden. Myeloid Syk-PI3Kg-HIF axis inhibits anti-tumor adaptive immunity: In silico design of a “first in class” novel dual-Syk/PI3K inhibitor, SRX3207, to block the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 109.