The complement system in glioblastoma multiforme

Abstract

The human complement system is represents the main effector arm of innate immunity and its ambivalent function in cancer has been subject of ongoing dispute. Glioma stem-like cells (GSC) residing in specific niches within glioblastomas (GBM) are capable of self-renewal and tumor proliferation. Recent data are indicative of the influence of the complement system on the maintenance of these cells. It appears that the role of the complement system in glial tumorigenesis, particularly its influence on GSC niches and GSC maintenance, is significant and warrants further exploration for therapeutic interventions.

Context-dependent roles of complement in cancer

“…Multiple reports show that these cells express also C3 and/or C5 and generate C3a and C5a, acting in an autocrine manner. The impact of the signaling is related to stimulation of proliferation 49,50 , multipotent state of glioblastoma glioma stem-like cells 51 , the epithelial to mesenchymal transition 52,53 , invasiveness and morphology alteration 54 , stemness etc. For example C3a enhanced cell proliferation, migration and stemness in cutaneous squamous cell carcinoma and this activity was correlated with activation of the Wnt and β-catenin pathway 55 .…”

“…The activation of B cells around high-risk gliomas is also likely, as indicated by the enrichment of a B cells related gene set, over-expressed in high risk compared to low risk glioma. Other studies also suggest that complement is activated in GBM, but the deleterious impact remains to be proven by in situ analyses 51,89 .…”

Complement: Bridging the innate and adaptive immune systems in sterile inflammation

“…In both development and disease, complement opsonins (i.e., C1q and C3b) facilitate microglia‐mediated synaptic pruning and phagocytosis of cellular debris 148‐151 and C1q can affect microglial cytokine production in a similar manner to that in DCs whereby apoptotic blebs modulate the response, although whether or not microglia interact with T cells in this manner is not known 152,153 . Likewise, anaphylatoxins (i.e., C3a and C5a) have a number of canonical effects on glial cells including driving chemotaxis, 154,155 promoting cytokine production, 156,157 and activating the inflammasome, 158,159 but may also have a number of direct effects on neurons including limiting excitotoxity, 160 promoting neurogenesis, 161 and driving neuronal stem cell proliferation in brain cancer 162 . Such diverse capabilities are also exhibited by MAC, which has canonical cytolytic effects that are driven in autoimmune conditions by autoantibody activation of the classical pathway 163‐166 and immunomodulatory and protective effects on glia 167,168 .…”

The Role of C1-Esterase Inhibitors in the Management of Vasogenic Edema in Glioblastoma

“…Data suggest that glioblastoma may use elements of the innate human complement system to further its spread, produce vasogenic edema, and enhance overall tumor maintenance through inhibition of antitumor inflammatory responses [3,4,7,8,18]. Our case demonstrates how plasma-derived C1INH, through the inhibition of the contact system, appears to be a successful means of controlling cutaneous angioedema as well as CNS edema.…”

“…Lanadelumab is a humanized monoclonal antibody against kallikrein having an approximate 15-day half-life and thus may not only be more specific but also have less of a drug burden than C1INH. At this time, however, it seems rational to investigate C1INH since it not only inhibits bradykinin production but also can control the complement system, both of which seem to be manipulated by the tumor [3,4,7,8,18].…”