Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma
Citations Over TimeTop 10% of 2021 papers
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.
Related Papers
- → CD200 and membrane protein interactions in the control of myeloid cells(2002)407 cited
- → Soluble Triggering Receptor Expressed on Myeloid Cells-1(2019)31 cited
- → Delineating Pro-Angiogenic Myeloid Cells in Cancer Therapy(2018)15 cited
- → Fc receptors on myeloid leukaemic cells: Comparison between assays of rosette-forming cells(1979)3 cited
- → Myeloid Cell Physiology and Disorders(2011)