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Cell metabolism

Cell metabolism

IF: 30.9
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PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T?cell immunotherapy.

Published:7 March 2023 DOI: 10.1016/j.cmet.2023.01.010 PMID: 36804058
Duo Zhang,?Albert M Li,?Guanghui Hu,?Menggui Huang,?Fan Yang,?Lin Zhang,?Kathryn E Wellen,?Xiaowei Xu,?Crystal S Conn,?Wei Zou,?Mark Kahn,?Seth D Rhoades,?Aalim M Weljie,?Serge Y Fuchs,?Nduka Amankulor,?Daniel Yoshor,?Jiangbin Ye,?Constantinos Koumenis,?Yanqing Gong,?Yi Fan

Abstract

The efficacy of immunotherapy is limited by the paucity of T?cells delivered and infiltrated into the tumors through aberrant tumor vasculature. Here, we report that phosphoglycerate dehydrogenase (PHGDH)-mediated endothelial cell (EC) metabolism fuels the formation of a hypoxic and immune-hostile vascular microenvironment, driving glioblastoma (GBM) resistance to chimeric antigen receptor (CAR)-T cell immunotherapy. Our metabolome and transcriptome analyses of human and mouse GBM tumors identify that PHGDH expression and serine metabolism are preferentially altered in tumor ECs. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T?cell infiltration into the tumors. PHGDH inhibition activates anti-tumor T?cell immunity and sensitizes GBM to CAR T therapy. Thus, reprogramming endothelial metabolism by targeting PHGDH may offer a unique opportunity to improve T?cell-based immunotherapy.

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