Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Abstract

Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration-and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…(2) TAMs that are recruited can either polarize into a continuum of macrophage states that are described with two extremes: an M1 (2a) or an M2 (2b) phenotype depending on the signal they receive (IFNg/LPS/GM-CSF for M1 and IL-4/IL-13/M-CSF for M2) Pyonteck et al, 2013;Kast et al, 2017;Roesch et al, 2018. (3) M1-like TAMs are macrophages with anti-tumor properties such as tumor cell kill abilities mediated by the production of NO, ROS, IFNg Kennedy et al, 2013;Leblond et al, 2017. They also mediate the Th1 response in the tumor through the activation of Th helper cells by secreting CXCL9, CXCL10, IL-12 Poon et al, 2017.…”

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

“…Interplay between the tumor and immune cells is an emerging key modulator of tumor biology and is a major determinant of pathogenesis and progression of many cancers, including glioma [27,31,42]. Moreover, profound immunosuppression occurs in the tumor microenvironment, particularly in the context of cell-mediated immunity [31], which is driven by an array of cytokines, such as prostaglandin E2, transforming growth factor beta (TGF-β), matrix metallopeptidase 9, IL-10, programmed death-ligand 1 (PD-L1), granulocyte colony stimulating factor, VEGF, and S100A4 [18,31,33,52,53]. At a mechanistic level, most proposed pathways to mediate immunosuppression in GBM are those involving signal transducer and activator of transcription 3 (STAT-3) [54,55], phosphoinositide 3 kinase, Ras-mitogen-activated protein kinase, wingless-related integration site/β-catenin, and indolamine 2, 3-dioxygenase [56].…”

The roles of CSFs on the functional polarization of tumor‐associated macrophages

“…G‐CSF, as GM‐CSF, is synthesized by unstimulated normal brain neurons , but its production is induced in numerous cell types upon activation (i.e., bone marrow stroma cells, endothelial cells, macrophages, and fibroblasts). G‐CSF is poorly detectable in the circulation, except in cases of infection or inflammation .…”