Abstract 170: Targeting of macrophage PI3Kγin prostate cancer using Eganelisib (IPI-549) reprograms immune-suppressive infiltrating macrophages to enhance anti-tumor immune responses and promote immunologically mediated tumor growth
Authors: Adusei Kenneth M. , Nirschl Thomas R. , Lee Alex J. , Shen Fan , Wang Xiaoxu , Praharaj Monali , Alvarez Jade , Gross Iyana , Lombardo Kara A. , Lotan Tamara L. , Varner Judith A. , Zarif Jelani C. 
Published: March 2024

Abstract
Background: Prostate cancer (PCa) is traditionally considered an immunologically 'cold’ indication, as evidenced in part by significant infiltration of immunosuppressive tumor associated macrophages (TAMs) and few activated effector CD8+ T cells. Attempts to (re)invigorate an anti-prostate cancer immune response with immune checkpoint blockade (ICB) such as anti-CTLA-4 and anti-PD-1 have been largely ineffective clinically, despite promising results in other cancers. This is likely due to a multitude of immunosuppressive cell types and secreted factors within the tumor microenvironment (TME) that diminish T cell activation and trafficking. Reducing the immunosuppressive burden intratumorally by targeting TAMs is a clinically attractive approach and offers opportunity to sensitize PCa to immune checkpoint blockade. While PI3K signaling is ubiquitous in most cell types, specific catalytic isoforms and regulatory elements are differentially expressed depending on cell type, with PI3Kγ being significantly enriched in myeloid cells and therefore offering a unique therapeutic opportunity for specific targeting.
Methods: Utilizing novel syngeneic prostate cancer tumors, PI3Kγ deletion and antagonism using Eganelisib (a small molecule inhibitor for PI3Kγ), we tested our hypothesis that targeting PI3Kγ signaling in PCa TAMs would lead to tumor growth inhibition and anti-tumor immune responses.
Results: We show here that PCa tumor cells do not express the PI3Kγ isoform and, therapeutic inhibition of PI3Kγ with Eganelisib reduces the TAM suppressive phenotype. We also show PI3Kγ signaling is essential to monocyte anti-apoptotic signaling, and inhibition of PI3Kγ can enhance anti-tumor immune responses in preclinical models of PCa. Specifically, inhibition of PI3Kγ alone is sufficient to enhance anti-tumor immune responses in the less aggressive B6CaP PCa model, but insufficient in the more aggressive RM-1 PCa model. However, treatment of RM-1 tumors with Eganelisib produces improved tumor control when combined with anti-PD-1 therapy, relative to Eganelisib or anti-PD1 as a monotherapy.
Conclusions: Altogether, these data highlight the integral role of PI3Kγ signaling in TAMs and the potential for therapeutic targeting with Eganelisib to sensitize PCa to ICB.
Citation Format: Kenneth M. Adusei, Thomas R. Nirschl, Alex J. Lee, Fan Shen, Xiaoxu Wang, Monali Praharaj, Jade Alvarez, Iyana Gross, Kara A. Lombardo, Tamara L. Lotan, Judith A. Varner, Jelani C. Zarif. Targeting of macrophage PI3Kγin prostate cancer using Eganelisib (IPI-549) reprograms immune-suppressive infiltrating macrophages to enhance anti-tumor immune responses and promote immunologically mediated tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 170.