Abstract
Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance.
Highlights
Glioblastoma (GBM) is the most common malignant brain tumor in adults [1,2]
One further possible resistance mechanism is the activation of alternative proangiogenic molecules like CXCL2 and IL8 that are secreted by tumor-associated microglia/macrophages (TAM) [25,26]
To assess general differences between primary and recurrent GBM and TMZ therapyinduced changes, we evaluated a total of 76 tissue samples from 38 GBM patients with matched primary and recurrent tumors (Table 1)
Summary
The standard of care therapy consists of surgical removal of the tumor, followed by concomitant radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ) [2,3,4] Even with this highly aggressive standard of care therapy, a median survival of only 15 months is achieved [5], since GBM is known for a rapid development of resistance to standard therapy with tumor recurrence [6,7,8,9,10]. One further possible resistance mechanism is the activation of alternative proangiogenic molecules like CXCL2 and IL8 that are secreted by TAMs [25,26] These chemokines and their respective receptor CXCR2 play a central role in GBM progression and are associated with a reduced OS [25,26,27,28]. They mediate tumor angiogenesis [25,29] and CXCR2 has been shown to be a driving force on the vascular mimicry (VM) formation in GBM patients, indicating a key role of this signaling pathway in the tumor blood supply [25,30]
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