Abstract 4656: Targeting macrophage PI3KGamma in aggressive prostate cancer

Abstract

Abstract The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family of lipid kinases play key roles in cancer biology by promoting cell motility, growth, and survival. Of the four class I PI3K isoforms, PI3Kα,β,δ,γ, the PI3Kγ isoform is primarily expressed by myeloid cells. Studies from the Varner lab have established that the macrophage lipid kinase, PI3Kγ, selectively promotes myeloid cell trafficking and immune suppressive transcription in tumor associated monocytes and macrophages, thereby inhibiting T cell recruitment, activation, and tumor eradication. We hypothesized that antagonism or deletion of PI3Kγ would induce tumor growth inhibition in vivo in prostate cancer (PCa) models. To test our hypothesis, we implanted syngeneic murine prostate cancer tumors (B6CaP) into global PI3Kγ knock out mice and preliminary studies show severe tumor growth inhibition. Using a publicly available single cell RNA sequencing database of metastatic PCa (mPCa) tumors from bone, we calculated regulon scores for transcription factors C/EBPβ and NFκB which are up and down-regulated by PI3Kγ signaling in myeloid cells respectively. This analysis indicated that a notable proportion of monocytes in mPCa have active PI3Kγ signaling based on C/EBPβ activity and a lack of NFκB activity. Finally, we tested the significance of eganelisib treatment on monocytes and found that this pathway was essential for monocyte survival during macrophage differentiation and adhesion. Altogether, our proposed research delineates the mechanistic roles of PI3Kγ in the regulation of prostate cancer tumor growth and support PI3Kγ as a target to sensitize PCa to immune checkpoint inhibitors. Citation Format: Kenneth M. Adusei, Thomas R. Nirschl, Alex J.-E. Lee, Fan Shen, Xiaoxu Wang, Jade Alvarez, Tamara L. Lotan, Judith Varner, Jelani Zarif. Targeting macrophage PI3KGamma in aggressive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4656.