Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma

Abstract

Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKβ, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKβ levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKβ expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype

“…Microglia and macrophages that accumulate in glioblastomas express MHC II as demonstrated previously (10, 41, 42). Moreover, we demonstrated that tumor-associated MDSCs exhibited higher expression of MHC II than did microglia and macrophages, confirming the recently described characteristics of MDSCs in a large cohort of glioblastoma patients (43).…”

Human glioblastoma‐associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples

“…The lack of genes related to "immune response/activation" in whole tumor tissues of high grade versus low grade glioma has previously been reported (Mieczkowski et al, 2015). This overlap includes genes related to "extracellular matrix organization" and "cell adhesion", but was primarily restricted to genes related to "mitotic cell cycle regulation".…”

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment

“…NF-kB signaling in immune cells is likely necessary for maintaining anti-tumor immunity. In one example, decreased levels of IKKβ in glioma-associated microglia/macrophages (GAMs) from glioblastoma multiforme correlated with impaired NF-κB dependent immune and inflammatory response (85). The dichotomy between promoting anti-cancer immunity and blocking tumor cell specific NF-kB signaling presents a conundrum for therapeutic targeting of this pathway, and further emphasizes the need to identify tumor-specific drivers to target.…”