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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbereabc8929
JournalScience Advances
Volume7
Issue number8
DOIs
StatePublished - Feb 17 2021

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma'. Together they form a unique fingerprint.

Cite this