Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response

Yao, Cheng-Cheng; Sun, Rui-Ming; Yang, Yi; Zhou, Haiyan; Meng, Zhouwenli; Chi, Rui; Xia, Lixue; Ji, Ping; Chen, Yingying; Zhang, Guoqing; Sun, Haipeng; Lü, Shun; Yang, Chen; Wang, Ying

doi:10.1016/j.celrep.2023.112186

Cited by 20 publications

(5 citation statements)

References 44 publications

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“…BCAAs include valine, leucine, and isoleucine which are essential for organisms 42, 43 . It has been shown that BCAAs activate T cell types via mTOR signaling and glucose metabolism 44, 45, 46 . BCAAs are metabolized into branched-chain α-keto acids (BCKAs) in e.g., the livers and muscles and play roles in immunity as well as BCAAs 42, 43, 47 .…”

Section: Resultsmentioning

confidence: 99%

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Nakamura,

Yoda,

Izumi

et al. 2023

Preprint

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Low albumin status is prevalent in advanced cancer patients, but the pathophysiology associated with this anomaly remains largely unexplored. To address this, we aim to search correlations of albumin levels with the transcriptome against peripheral blood mononuclear cells and the plasma metabolome within the same patients having metastatic breast cancers. We confirm that metastatic breast cancer patients exhibit low albumin levels in varying degrees without prominent systemic inflammation. Our data demonstrate that low albumin levels correlate with transcriptome signatures indicative of neutrophil activation and T-cell down-regulation, an immunosuppressive phenotype. We also find that immunoregulatory metabolites, such as arginine, are reduced in plasma in an albumin-correlated manner, further corroborating systemic immunosuppression. These results are verified using a mouse model of breast cancer. We conclude that low albumin status in metastatic breast cancer patients accompanies immunosuppressive phenotypes, which is likely unfavorable for anti-cancer immunotherapy and thus can be a cause of unsuccessful treatment outcomes.

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Section: Resultsmentioning

confidence: 99%

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Nakamura,

Yoda,

Izumi

et al. 2023

Preprint

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Section: Amino Acid Metabolism In the Tumor Microenvironment (Tme)mentioning

confidence: 99%

“…266,267 Also, BCAA supplementation can increase CD8 + T cells to upregulate glucose transporter GLUT 1 in a FoxO1-dependent manner, increase glucose uptake and utilization, and enhance the antitumor activity of CD8 + T cells, having a synergistic role with anti-PD-1 therapy. 268 There is a subset of immunomodulatory B cells in the TME with TGF-β1 as the main regulatory feature and expressing Leu-tRNAsynthase 2 (LARS2). This subpopulation of LARS B cells shows a preference for Leu metabolism, which can be induced by a Leu diet to promote mitochondrial NAD + production and oxidative metabolism and recruit NAD + -dependent protein deacetylase SIRTUIN-1 (SIRT1) to participate in the regulation of LARS B cells.…”

Section: Bcaamentioning

confidence: 99%

“…Subsets with different preferences for BCAA metabolism have also been found in breast cancer, and further studies are needed to determine whether this is due to differences in tumor cells or the involvement of other cells in the microenvironment. 55,59 BCAA metabolism is equally important for the function of proinflammatory CD4 + and CD8 + T cells and immunosuppressive regulatory Treg cells, 41,[265][266][267][268][269][270][271][272] which plays key role in metabolic diseases, liver and kidney diseases. 10,11,[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]345,346 Currently, drugs targeting BCAA uptakedependent amino acid transporter LAT1 metabolic enzymes BCAT and BCKDK are in trials.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Amino acid metabolism in health and disease

Ling,

Jiang,

et al. 2023

Sig Transduct Target Ther

104

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Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.

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“…Depriving glucose or inhibiting glycolysis with 2-DG can selectively inhibit the production of IFN-γ, but not IL-2 [ 64 , 65 ]. In mouse CD8 + T cells, branched-chain amino acids (BCAA) accumulation increases cellular glycolysis and OXPHOS through FOXO1-dependent upregulation of GLUT1 level, thereby enhancing the anti-tumor immune function of CD8 + T cells., while BCAA supplementation also helps to improve the clinical efficacy of anti-PD-1 immunotherapy on tumors [ 66 ]. After activation of mouse CD8 + T cells using the pan-β-adrenergic receptor (AR) agonist isoprenaline (ISO), assays showed a decrease in their GLUT1 expression, and further studies revealed a significant decrease in glucose uptake and glycolysis compared with non-ISO activated CD8 + T cells, as well as impaired mitochondrial function, ultimately inhibiting CD8 + T cell activation and effector functions [ 67 ].…”

Section: Effects Of Altered Glycolysis Levels On Cd8 + ...mentioning

confidence: 99%

Effects of altered glycolysis levels on CD8+ T cell activation and function

et al. 2023

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CD8+ T cells are an important component of the body’s adaptive immune response. During viral or intracellular bacterial infections, CD8+ T cells are rapidly activated and differentiated to exert their immune function by producing cytokines. Alterations in the glycolysis of CD8+ T cells have an important effect on their activation and function, while glycolysis is important for CD8+ T cell functional failure and recovery. This paper summarizes the importance of CD8+ T cell glycolysis in the immune system. We discuss the link between glycolysis and CD8+ T cell activation, differentiation, and proliferation, and the effect of altered glycolysis on CD8+ T cell function. In addition, potential molecular targets to enhance and restore the immune function of CD8+ T cells by affecting glycolysis and the link between glycolysis and CD8+ T cell senescence are summarized. This review provides new insights into the relationship between glycolysis and CD8+ T cell function, and proposes novel strategies for immunotherapy by targeting glycolysis.

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Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response

Cited by 20 publications

References 44 publications

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Amino acid metabolism in health and disease

Effects of altered glycolysis levels on CD8+ T cell activation and function

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