Metabolic Reprogramming of Tumor Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancer Tumors

Glutamine metabolism in the tumor microenvironment is a critical regulator of 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). Additionally, we show JHU083-mediated glutamine antagonism in the tumor microenvironment induces TNF, pro-inflammatory, and mTORC1 signaling in different 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 disruption in purine metabolism. Although the effect of glutamine antagonism was less profound on tumor-infiltrating T cells for their anti-tumor activity, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a global 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.

Note:
Funding Information: This work was supported by the Bloomberg∼Kimmel Institute for Cancer Immunotherapy (J.C.Z.), Prostate Cancer Foundation Young Investigator award (J.C.Z.), National Institutes for Health, United States/National Cancer Institute, United States K22 CA237623 award (J.C.Z.), Maryland Cigarette Restitution Fund grant FHB33CRF (J.C.Z.) and NIH R01CA229451 (B.S.S).

Declaration of Interests: Authors B.S.S., J.P., R.D.L, R.R., and J.A. are inventors of patent applications filed by Johns Hopkins Technology Ventures covering novel glutamine antagonists, including JHU083, and their utility which has been licensed to Dracen Pharmaceuticals. B.S.S., J.P., and R.R. are also a co-founders and consultants for Dracen Pharmaceuticals. This arrangement has been reviewed and approved by Johns Hopkins University following their respective conflicts of interest policies.

Ethical Approval Statement: All procedures and protocols performed in this study involving animals 95 strictly followed US NIH guidelines and were approved by the Johns Hopkins Medical Institutions 96 Animal Care and Use Committee.

Keywords: tumor associated macrophages, macrophages, glutamine, JHU083, prostate cancer, bladder cancer

Suggested Citation: Suggested Citation

Praharaj, Monali and Shen, Fan and Lee, Alex J. and Zhao, Liang and Nirschl, Thomas R. and Theodros, Debebe and Singh, Alok K. and Wang, Xiaoxu and Adusei, Kenneth M. and Lombardo, Kara and Williams, Raekwon A. and Sena, Laura A. and Thompson, Elizabeth and Tam, Ada and Yegnasubramanian, Srinivasan and Pearce, Edward J. and Leone, Robert D. and Alt, Jesse and Rais, Rana and Slusher, Barbara S. and Pardoll, Drew M. and Powell, Jonathan D. and Zarif, Jelani C., Metabolic Reprogramming of Tumor Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancer Tumors. Available at SSRN: https://ssrn.com/abstract=4506054 or http://dx.doi.org/10.2139/ssrn.4506054

This version of the paper has not been formally peer reviewed.