Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

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.

Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

“…GSCs express various molecules that deliver either stimulatory or inhibitory signals during direct physical contact with tumor-infiltrating lymphocytes (TILs). The balance of these opposing signals regulates the amplitude and quality of TIL response and the aberrant activation of the inhibitory signals, also known as immune checkpoints, is a mechanism utilized by cancer cells to evade immune attacks [ 43 , 68 ].…”

Combining TMZ and SB225002 induces changes of CXCR2 and VEGFR signalling in primary human endothelial cells in vitro

“…GBM (6). Chemokine signalling axes, for instance the CXCR2 signalling pathway, have been investigated in preclinical in vitro and in vivo experimental models as well as in GBM patient ex vivo samples (11,18,19,24). As CXCR2 is expressed by glioma cells as well as endothelial cells and overexpression of its ligands CXCL2 and IL8 is associated with a reduced patient survival (11,18,(25)(26)(27)(28), this signalling pathway is a feasible target for GBM therapy.…”

“…Based on the studies aforementioned, combining CXCR2-antagonisation with the standard-of-care TMZ therapy appears promising. In another previous study by the authors, it was demonstrated that a combination therapy in vivo, consisting of TMZ and SB, reduced tumour volume in immunocompetent mice (19). However, little is known about the molecular changes during treatment with the combination therapy.…”

“…A number of these novel therapeutic approaches target the tumour microenvironment (6,(9)(10)(11), that includes endothelial cells, pericytes, immune cells and particularly tumour-associated microglia/macrophages which make up to 30-50% of the tumour mass (12)(13)(14)(15)(16). They secrete soluble factors such as growth factors and chemokines and support tumour growth e.g., by initiating the formation of new blood vessels, the proliferation of tumour cells and by expressing immuno-suppressive molecules (12)(13)(14)(15)(17)(18)(19)(20). For instance, VEGF is one of the most important proangiogenic growth factors in GBM (21,22).…”

Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities

“…Among the stromal cells, TAMs are the most abundant ones and are important contributors to disease progression [ 7 , 8 ]. Previous studies showed a positive correlation between the abundance of TAMs and glioma grade and a negative correlation with survival [ 9 , 10 ]. Immunotherapies such as immune checkpoint inhibitors and CAR T cells are effective for a subset of hematological malignancies but have not shown efficacy in GBM and other solid tumors [ 11 ].…”