Expression Profiling of Primary and Recurrent Glioblastomas Reveals a Reduced Level of Pentraxin 3 in Recurrent Glioblastomas

Abstract

Glioblastomas (GBM) are highly infiltrative tumors and despite intensive treatment tumor recurrence is inevitable. The immune microenvironment in recurrent GBM is poorly characterized, but it is potentially influenced by therapeutic interventions with surgery, radiotherapy, and chemotherapy. The aim of this study was to obtain a deeper insight in the immune microenvironment in primary and recurrent GBM. Primary and recurrent glioblastoma samples from 18 patients were identified and expression profiling of 770 myeloid innate immune-related markers was performed. Leukemia inhibitory factor and pentraxin 3 were expressed at lower levels in recurrent tumors. Using in silico data and immunohistochemical staining, this was validated for pentraxin 3. Both high leukemia inhibitory factor and pentraxin 3 expression appeared to be associated with shorter survival in primary and recurrent GBM using in silico data. In primary GBM, gene set analysis also showed higher expression of genes involved in metabolism, extracellular matrix remodeling and complement activation, whereas genes involved in T cell activation and checkpoint signaling were expressed at higher levels in recurrent GBM. The reduced level of pentraxin 3 in recurrent glioblastomas and the gene set analysis results suggest an altered microenvironment in recurrent GBM that might be more active.

The presence of TIM‐3 positive cells in WHO grade III and IV astrocytic gliomas correlates with isocitrate dehydrogenase mutation status

“…The processes of counterstaining, coverslipping, and slide digitization were performed as described above. Automated digital image analysis and quantification were done in the Visiopharm APP author module as previously described (64, 65). Output variables were percentages of positive area, defined as the area of positive expression divided by the total area of interest multiplied by 100.…”

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas

“…Petterson et al, compared the gene expression between paired pGBMs and rGBMs based on the RNA obtained from formalin-fixed paraffin-embedded (FFPE) tissue sections [26]. Gene set enrichment analysis suggested the expression of genes involved in metabolism, extracellular matrix (ECM) remodeling, and complement activation are lower in rGBMs than pGBMs.…”

“…Instead, genes related to T cell activation and checkpoint signaling were high in rGBM, suggesting T cell activation is part of the event that promotes the recurrence of GBM progression (we will discuss how this affects GBM in a later part). Moreover, they compared early recurring tumors (shorter than 14 months after primary treatments) with late recurring tumors (longer than 14 months after primary treatments) and found that genes involved in ECM remodeling, angiogenesis, and growth factor signaling are expressed higher, and genes related to Th2 cell activation, chemokine signaling, and tolllike receptor (TLR) are lower in tumors with early recurrence [26]. The differentially expressed genes between early-and late-recurrent tumors must provide useful information for predicting the patient outcome.…”

“…They demonstrated that GBM cells epigenetically change their gene expression profiles upon exposure to interferon-γ (IFN-γ), a known important effector molecule of anti-tumor immunity [10]. Several researchers have reported a high proportion of T cells in rGBM [17,26,32]. These findings may give us a caution in therapy-mediated reactivation of cytotoxic lymphocytes that triggers the production of IFN-γ, granzymes, and perforin, because they possibly affect the immune evasion capabilities of rGBM cells by inducing myeloid mimicry deployment.…”

Insights into the Relationship between Pentraxin-3 and Cancer

“…Increased synthesis of inflammatory biomarkers and activation of chemokine receptors (mediated through IL-6, IL-8, CX3CL1), leukocyte and stromal cells recruitment, induction of reactive oxidative species, hypoxia, and necrosis have been also identified in glioblastomas—highly aggressive astrocytic tumors [ 45 , 63 ]. Glioma represents one of the most common and lethal tumors in middle-aged and elderly individuals with a poor prognosis due to rapid cellular infiltration and invasiveness [ 64 , 65 ]. Unfortunately, tumor recurrence appears despite tumor resection, intensive healthcare, and treatment [ 63 , 65 ].…”