Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Abstract

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

• Authors: Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif
• Journal: Cancer immunology research (Cancer Immunol Res) (May 03 2024) ISSN: 2326-6074 [Electronic] United States
• PMID: 38701369 (Publication Type: Journal Article)