Inhibition of Glutamine Utilization Synergizes with Immune Checkpoint Inhibitor to Promote Antitumor Immunity

Byun, Jun‐Kyu; Park, Mihyang; Lee, Seunghyeong; Yun, Jae Won; Lee, Jaebon; Kim, Jae Sun; Cho, Sung Jin; Jeon, Hui-Jeon; Lee, Inkyu; Choi, Youn‐Hee; Park, Keun-Gyu

doi:10.1016/j.molcel.2020.10.015

Cited by 129 publications

(110 citation statements)

References 61 publications

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“…It is reasonable to speculate that the downregulation of MAPK9 in ESCC might facilitate carcinogenesis through inhibiting B7.1-mediated activation of immune responses. In addition, restriction of glutamine utilization could enhance anti-programmed death ligand-1 (PD-L1) levels in tumor, which promote the effectiveness of PD-L1 antibody ( Byun et al, 2020 ). Therefore, we hypothesized that SLC38A1, a key transporter of glutamine, might block the effectiveness of PD-L1 antibody by stimulating glutamine metabolism in ESCC.…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

Song

Yan-hu

Gao

et al. 2021

Front. Mol. Biosci.

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Esophageal squamous cell carcinoma (ESCC) accounts for the main esophageal cancer (ESCA) type, which is also associated with the greatest malignant grade and low survival rates worldwide. Ferroptosis is recently discovered as a kind of programmed cell death, which is indicated in various reports to be involved in the regulation of tumor biological behaviors. This work focused on the comprehensive evaluation of the association between ferroptosis-related gene (FRG) expression profiles and prognosis in ESCC patients based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). ALOX12, ALOX12B, ANGPTL7, DRD4, MAPK9, SLC38A1, and ZNF419 were selected to develop a novel ferroptosis-related gene signature for GEO and TCGA cohorts. The prognostic risk model exactly classified patients who had diverse survival outcomes. In addition, this study identified the ferroptosis-related signature as a factor to independently predict the risk of ESCC. Thereafter, we also constructed the prognosis nomogram by incorporating clinical factors and risk score, and the calibration plots illustrated good prognostic performance. Moreover, the association of the risk score with immune checkpoints was observed. Collectively, the proposed ferroptosis-related gene signature in our study is effective and has a potential clinical application to predict the prognosis of ESCC.

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Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

Song

Yan-hu

Gao

et al. 2021

Front. Mol. Biosci.

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“…Sheng et al [88]found that mutation of calcium voltage-gated channel subunit alpha1 E(CACNA1E) reduced PD-1/PD-L1/PD-L2 expression in HCC. Byun et al [89] reported that activated calcium/NF-κB signaling, which resulted from impaired SERCA activity by reduced cellular GSH levels, upregulates PD-L1 expression. Consistently, inhibition of proprotein convertases blocked proteolytic maturation of the Notch precursor, inhibited calcium/NFAT and NF-κB signaling, and enhanced ERK activation, thus repressing PD-1 expression [90].…”

Section: Calcium Signaling Regulates Immune Checkpointsmentioning

confidence: 99%

Calcium signaling in cancer progression and therapy

Lian

Zhao

2021

The FEBS Journal

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VGCCs voltage-gated calcium channels SOCE store-operated calcium entry CRAC calcium release-activated Ca 2+ TRP Transient receptor potential ER endoplasmic reticulum SR sarcoplasmic reticulum IP3 inositol 1,4,5-trisphosphate GPCRs G-protein-coupled receptors MCU mitochondrial calcium uniporter CaMKII Ca 2+ -calmodulin-dependent protein kinase II CACNA1E calcium voltage-gated channel subunit alpha1 E CCBs calcium channel blockers

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“…The inhibition of glutamine use in lung and colon tumors increased the expression of PD-L1 by reducing GSH levels. The reduction in GSH levels inhibited sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) activation and increased cytosolic Ca 2+ levels and CaMKII phosphorylation, which further activated the downstream nuclear factor-kappa B (NF-κB) signalling pathway to promote the expression of PD-L1 ( 62 ). However, researchers found that glutamine deprivation in renal cancer cells can weaken an immunosuppressive TME.…”

Section: Tumor Glutamine Metabolism and Immune Escapementioning

confidence: 99%

“…However, one study found that deprivation of glutamine in the culture medium upregulate the expression of PD-L1 in renal cancers ( 61 ). In addition, it has been proved that targeting of glutamine metabolism can upregulate the expression of PD-L1 in lung cancer and colon cancer ( 62 ). Therefore, the targeting of glutamine metabolism in combination with PD-L1-targeted ICIs may produce a more powerful therapeutic effect in the future.…”

Section: Strategies Targeting Glucose or Glutamine Metabolism In Combination With Pd-1/pd-l1 Checkpoint Blockade Immunotherapy For Tumor mentioning

confidence: 99%

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

Zhang

et al. 2021

Front. Oncol.

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Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

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Inhibition of Glutamine Utilization Synergizes with Immune Checkpoint Inhibitor to Promote Antitumor Immunity

Cited by 129 publications

References 61 publications

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

Calcium signaling in cancer progression and therapy

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

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