Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma

Abstract

Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions.

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

“…These efforts have resulted in the identification of multiple molecular pathways involved in the pathogenesis of ACP [6]. A number of these pathways result in the upregulation of pro-inflammatory/immune genes that may be amenable to targeted therapies [10,11,[31][32][33]. The immune/inflammatory cells seen in ACP samples are varied and can include CD4-T-Lymphocytes, CD20-B-Lymphocytes, CD-68-Macrophages, and CD-56-NK cells.…”

“…In another study, Donson et al [31] used cytometric bead analysis to measure the concentration of 24 cytokines and 11 chemokines in cyst fluid from five pediatric ACPs and five pediatric pilocytic astrocytomas (PAs). Their analysis demonstrated that six cytokines were present at statistically significant increased levels in ACPs versus PAs.…”

Adamantinomatous craniopharyngioma: moving toward targeted therapies

“…Intracystic catheter insertion via stereotactic and/or endoscopic techniques has been reported as a means to effectively drain cystic tumors. 27,35 However, intracystic therapies appear to represent a temporary solution, as demonstrated by high rates of recurrence of cystic tumor symptoms within a relatively short period of time, 19,53 especially as the neurosurgery and neuro-oncology communities increasingly recognize ACP as a chronic disease. As such, current direct intracystic therapies, such as interferon (IFN), bleomycin, and radioisotopes, play a role in ACP control but in most cases are not long-term tumor control solutions.…”

“…2). 19,25,50 Cyst fluid characterization has also revealed elevated concentrations of IDO-1, an immunosuppressant, 19 and the presence of β-thymosins, peptides with antiapoptotic and antiinflammatory properties. 18 The translation of these findings through the application of directed antiinflammatory therapies targeting IL-6 has begun to show promise for the treatment of ACP.…”

“…22 These agents are well tolerated in humans, including children, and have regulatory approval in the US and Europe. 19,41,70 The efficacy of tocilizumab in the treatment of ACP is currently being investigated under a phase 0 clinical trial (NCT03970226) and was recently reported to demonstrate efficacy in 2 patients treated on a compassionate use basis. 24 A multicenter phase II trial of IL-6 inhibition for patients with ACP is also under development.…”