PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy

Zhang, Duo; Li, Albert M.; Hu, Guanghui; Huang, Menggui; Fan, Yan; Zhang, Lin; Wellen, Kathryn E.; Xu, Xiaowei; Conn, Crystal S.; Zou, Wei; Kahn, Mark B.; Rhoades, Seth D.; Weljie, Aalim M.; Fuchs, Serge Y.; Amankulor, Nduka; Yoshor, Daniel; Ye, Jiangbin; Koumenis, Constantinos; Gong, Yanqing; Fan, Yi

doi:10.1016/j.cmet.2023.01.010

Cited by 52 publications

(34 citation statements)

References 94 publications

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“…The rapid proliferation of GBM cells occurs simultaneously with the delayed development of the tumor vasculature, creating a hypoxic environment within the tumor 32 , 33 . The hypoxic state frequently precipitates necrotic tissue formation in the central region of the GBM tumor, thereby establishing a distinctive hallmark that sets it apart from other benign intracranial tumors.…”

Section: Resultsmentioning

confidence: 99%

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse

Zhang,

Xi,

et al. 2024

Nat Commun

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

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Section: Resultsmentioning

confidence: 99%

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse

Zhang,

Xi,

et al. 2024

Nat Commun

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“…Blocking IMPDH may still have therapeutic benefit in glioma with a favorable therapeutic ratio because of the preference for gliomas to salvage hypoxanthine. Restricting dietary serine could help slow GBM growth and potentially augment the efficacy of standard of care GBM treatments 51 , though the efficacy of this approach could be limited by local production of serine in the GBM microenvironment 52 .The patient-to-patient heterogeneity in environmental serine dependence we observed suggests that isotope tracing could be used a precision medicine technique to determine which patients are mostly likely to benefit from dietary serine restriction.…”

Section: Discussionmentioning

confidence: 98%

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott,

Mittal,

Meghdadi

et al. 2023

Preprint

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The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.

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“…204 Studies have revealed that inhibitors targeting PHGDH suppress the proliferation and reduce the growth of xenografts, especially in PHGDHdependent cancer cell lines. 205 Therefore, targeting the SSP is a promising strategy for cancer treatment. Furthermore, cancers with amplified SSP enzymes are not readily influenced by a lack of exogenous serine; however, p53 depletion may aggravate this dependency.…”

Section: Prospective and Challenges Of Targeting 1c Metabolismmentioning

confidence: 99%

“…In tumours with upregulated SSP activity, the depletion of SSP enzymes can suppress the proliferation and growth of cancer cells 204 . Studies have revealed that inhibitors targeting PHGDH suppress the proliferation and reduce the growth of xenografts, especially in PHGDH‐dependent cancer cell lines 205 . Therefore, targeting the SSP is a promising strategy for cancer treatment.…”

Section: Prospective and Challenges Of Targeting 1c Metabolismmentioning

confidence: 99%

Targeting one‐carbon metabolism for cancer immunotherapy

Ren,

Wang,

Zheng

et al. 2024

Clinical & Translational Med

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BackgroundOne‐carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune‐related adverse events in patients.MethodsWe collected numerous literatures to explain the roles of one‐carbon metabolism in cancer immunotherapy.ResultsIn this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future.ConclusionTargeting one‐carbon metabolism is useful for cancer immunotherapy.

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PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy

Cited by 52 publications

References 94 publications

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Targeting one‐carbon metabolism for cancer immunotherapy

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