Pharmacological targeting of the tumor-immune symbiosis in glioblastoma

Abstract

Glioblastoma (GBM) is the most common and highly lethal form of primary brain tumor in adults. The median survival of GBM patients is approximately 14-16 months despite multimodal therapies. Emerging evidence has substantiated the critical role of symbiotic interactions between GBM cells and noncancerous immune cells (e.g., myeloid cells and T cells) in regulating tumor progression and therapy resistance. Approaches to target the tumor-immune symbiosis have emerged as a promising therapeutic strategy for GBM. Here, we review the recent developments for pharmacological targeting of the GBM-immune symbiosis and highlight the role of such strategies to improve the effectiveness of immunotherapies in GBM.

Keywords: glioblastoma; immunotherapy; macrophages; microglia, MDSCs; symbiosis.

Figure 1.. Pharmacological approaches to target the GBM–GAM crosstalk.

Depending on targeted cell types and molecular mechanisms underlying the GBM–GAM symbiosis, pharmacological strategies of targeting the symbiosis include: (i) targeting receptors on GBM cells; (ii) targeting receptors on GAMs; (iii) targeting GBM cell-secreted chemokines; (iv) targeting GAM-secreted factors; and (v) trapping extracellular signaling in the TME. The key targets and associated drug candidates are indicated. Abbreviations: 4-1BB, tumor necrosis factor receptor superfamily member 9; ARS2, arsenite-resistance protein 2; AXL, AXL receptor tyrosine kinase; BACE1, β-site amyloid precursor protein-cleaving enzyme 1; CHI3L1, chitinase-3-like 1; CLOCK, circadian locomotor output cycles kaput; COX-2, cyclooxygenase-2; GAMs, glioma-associated macrophages and microglia; CSF-1R, colony-stimulating factor-1 receptor; GBM, glioblastoma; Gal3BP, galectin 3-binding protein; LOX, lysyl oxidase; MAGL, monoacylglycerol lipase; OPN, osteopontin; PGE₂, prostaglandin E₂; PI3Kγ, phosphoinositide-3-kinase gamma; PROS1, Protein S; PTPRZ1, tyrosine phosphatase receptor type Z1; SLIT2, slit guidance ligand 2; TME, tumor microenvironment; TβRI, transforming growth factor beta receptor I; WISP1, Wnt-induced signaling protein 1.

Figure 2.. Pharmacological tools to target the GBM–MDSC symbiosisw.

GBM cell-derived ligands, exosomes, and cytokines recruit and activate MDSCs, which, in turn, inhibit T cell proliferation and function and promote GBM tumor growth. Pharmacological approaches targeting MDSC infiltration and activation during the GBM–MDSC symbiosis are proposed. The key targets and associated drug candidates are indicated. Sexual dimorphism of MDSCs also appears to be a target for GBM therapy: low dose of chemotherapy (fludarabine and capecitabine) inhibits M-MDSC proliferation in male GBM. By contrast, anti-IL-1β treatment inhibits PMN-MDSC function and enhances CD8⁺ T cell-mediated antitumor immunity in female GBM. Abbreviations: 2-ME2, 2-Methoxyestradiol; CCL2, C-C motif chemokine ligand 2; CCR2/4, C-C motif chemokine receptor 2/4; CLXCL1/2, C-X-C motif ligand 1/2; DUSP3, dual specificity phosphatase 3; ERK, extracellular signal-regulated kinase, GAMs, glioma-associated macrophages and microglia; GBM, glioblastoma; IL-1β/R, interleukin-1β/receptor; INFγ, interferon gamma; MIF, macrophage migration inhibitory factor; M-MDSCs, monocytic myeloid-derived suppressor cells; OPG, osteoprotegerin, PMN-MDSC, polymorphonuclear myeloid-derived suppressor cells.

Figure 3.. Workflow of developing pharmacological tools for targeting the glioblastoma (GBM)-immune symbiosis.

Spatial tissue characterization and disease-specific analyses are critical for establishing the immune landscape of GBM patient tumors with different tumor origins, genetic statues, disease stages, and immunotherapeutic responses. The immune and genetic landscapes of specific GBM tumors can be determined via flow cytometry/fluorescence-activated cell sorting (FCM/FACS), single-cell RNA sequencing (scRNA-seq), whole-exome seq, T cell receptor (TCR)-seq, and mass cytometry (CyTOF). Integration of these techniques could help identify and determine the relationships between GBM cell genetic statues and immune landscape, and their association with tumor progression and the effectiveness of immunotherapies. Unbiased profiling (e.g., scRNA-seq, RNA-seq, and microarray) and its associated pathway analysis followed by in vitro and in vivo functional studies are essential for validating which pathways and factors are crucial for the context-dependent GBM–immune crosstalk. Network pharmacological studies and molecular docking could help to identify novel therapeutic drug candidates, such as neutralizing antibodies (Abs) and small-molecule agonists/antagonists, for translational studies.