TMIC-38. MITOCHONDRIAL ATP BIOGENESIS REGULATED BY VDAC1 IN TMEM119+ TUMOR-ASSOCIATED MICROGLIA AND MACROPHAGES MEDIATES HIGH-GRADE GLIOMA GROWTH

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-11, Vol.25 (Supplement_5), p.v286-v286
• Main Authors: Wu, Caren, Chen, Yiyun, Lin, Ya-Jui, Wei, Kuo-Chen, Chang, Kwang-Yu, Feng, Li-Ying, Wu, An-Chih, Chen, Ko-Ting, Ren, Alexander Liang, Nitta, Ryan, Wu, Janet, Pant, Ayush, Cho, Kwang Bog, Mackall, Crystal, Chuang, Jian-Ying, Huang, Chiung-Yin, Li, Gordon, Jackson, Christopher, Chen, Pin-Yuan, Lim, Michael
• Format: Article
• Language: English
• Subjects: Tumor Microenvironment
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad179.1104

Abstract Patients with high-grade glioma have a poor prognosis and an average survival of less than 15 months, which is associated with an increase in tumor-associated microglia and macrophages (TAMs). TAMs in the glioma microenvironment are traditionally thought to suppress antitumor immune responses and are metabolically reprogrammed by glioma. However, it is unknown whether metabolic processes, like ATP synthesis, in TAMs can directly affect glioma growth. Through RNAseq, we identified a novel subpopulation that had elevated metabolic expression patterns. These TAMs (TMEM119+) had increased protein expression of ATP synthases and VDAC1, and surprisingly only TAMs located within the tumor center had increased mitochondrial energy potential. In vitro and ex vivo co-culture assays determined that activated TAMs increased the expression of metabolic, growth, and survival genes in high-grade glioma cells. These activated TAMs produced higher levels of extracellular ATP, which in turn increased glioma cell viability. Inhibition studies identified P2X purinoceptor 7 (P2X7R) as a key player in the TAMs ATP-induced glioma survival. Our findings demonstrate for the first time that a subpopulation of TAMs induced a more tumorigenic microenvironment through the secretion of ATP.