PHGDH Inhibition Overcomes Glioblastoma Resistance to T-cell Therapy

Aberrant vasculature is a common feature of an immunosuppressive tumor microenvironment that hinders efficient T-cell infiltration. Given that glioblastomas (GBM) exhibit a highly vascularized tumor microenvironment and are largely resistant to T cell–based immunotherapies, Zhang and colleagues explored how tumor-associated endothelial cells (EC) within the vasculature may contribute to an immune-hostile environment. RNA sequencing and metabolite set enrichment analysis were used to assess the differences between human ECs isolated from glioma biopsies or normal brains and revealed that tumor ECs display high levels of serine metabolism and upregulate PHGDH, which encodes phosphoglycerate dehydrogenase, a rate-limiting enzyme for de novo serine synthesis. Single-cell RNA sequencing analysis of tumors from mice orthotopically injected with murine GBM cells suggested an important role of PHGDH in promoting the cell cycle and proliferation, specifically in tumor ECs but not in normal ECs or tumor cells, while stable isotope–labeled glucose tracing analysis of tumor ECs demonstrated that PHGDH likely supports proliferation by promoting nucleotide biosynthesis and redox homeostasis. In line with these findings, PHGDH inhibition slowed tumor EC proliferation in vitro and reduced tumor EC outgrowth and sprouting when cocultured with glioma cells ex vivo. When murine GBM cells were injected into control mice or mice harboring an EC-specific heterozygous knockout of Phgdh, Phgdh loss pruned the tumor vasculature into a well-organized structure, enhanced T-cell infiltration, and improved survival. Moreover, systemic pharmacologic inhibition of PHGDH not only recapitulated these effects on vessel pruning and infiltration of activated T cells but also sensitized two different murine GBM models expressing mutant EGFR^vIII to EGFR^vIII-targeted chimeric antigen receptor (CAR)–T cell therapy. Taken together, this study uncovers the function of PHGDH in promoting an EC-driven immunosuppressive microenvironment and provides preclinical support for targeting PHGDH to enhance the efficacy of CAR-T cell therapy in GBM.

Zhang D, Li AM, Hu G, Huang M, Yang F, Zhang L, et al. PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy. Cell Metab 2023 Feb 17 [Epub ahead of print].

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