Abstract

Simple SummaryResistance to standard therapies impose a huge challenge on the treatment for glioblastoma multiforme (GBM), which is often considered as a cell intrinsic property of either GBM or, more significantly, of GBM stem-like cells. Tumor-associated macrophages and microglia (TAMs) take up the majority of the immune population in the tumor microenvironment of GBM and potentially participating in modulating therapy responses. However, little is known about the mechanisms underlying the effect of TAMs on temozolomide (TMZ) induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important participants in the process of intercellular communications in the tumor microenvironment. Herein, we revealed a novel concept of an intra-tumoral ADAM8 mediated malignant positive feedback loop constituted by the intimate interaction of tumor associated macrophages (TAMs) and GBM cells under TMZ treatment. These findings provide a convincing example and further support the notion that the tumor microenvironment, in addition to GBM cells and GBM stem-like cells, should be considered as an essential modulator of therapy in GBM. In conclusion, our study provides a rational basis for TAM sparing ADAM8-targeting in GBM to optimize standard chemotherapy.AbstractStandard chemotherapy of Glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to acquired chemoresistance. Tumor-associated macrophages and microglia (TAMs) as major immune cell population in the tumor microenvironment are potential modulators of TMZ response. However; little is known about how TAMs participate in TMZ induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important mediators of cellular communication in the tumor microenvironment. A qPCR screening was performed to identify potenti