Data from Glioblastoma Cell–Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance

Abstract

<div>Abstract<p>Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (<i>lnc-TALC</i>) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that <i>lnc-TALC</i> could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of <i>lnc-TALC</i> binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited <i>lnc-TALC</i>–mediated TMZ resistance. Our results reveal that exosome-transmitted <i>lnc-TALC</i> could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the <i>lnc-TALC</i>–mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.</p><p><i>See related Spotlight by Zhao and Xie, p. 1372.</i></p></div>