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
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...
May 3, 2024: Cancer Immunology Research