Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma.

Abstract

Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8+ T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution.

• Authors: Jason Miska, Aida Rashidi, Catalina Lee-Chang, Peng Gao, Aurora Lopez-Rosas, Peng Zhang, Rachel Burga, Brandyn Castro, Ting Xiao, Yu Han, David Hou, Samay Sampat, Alex Cordero, Joshua S Stoolman, Craig M Horbinski, Mark Burns, Yana K Reshetnyak, Navdeep S Chandel, Maciej S Lesniak
• Journal: Science advances (Sci Adv) Vol. 7 Issue 8 (02 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 33597238 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• Polyamines
• Eflornithine

Topics

• Animals
• CD8-Positive T-Lymphocytes (metabolism)
• Cell Survival
• Eflornithine (metabolism, pharmacology)
• Glioblastoma (metabolism)
• Hydrogen-Ion Concentration
• Immunosuppression Therapy
• Mice
• Myeloid Cells (metabolism)
• Polyamines (metabolism)
• Tumor Microenvironment