Lactate supports a metabolic-epigenetic link in macrophage polarization

Noe, Jordan T.; Rendon, Beatriz E.; Geller, Anne E; Conroy, Lindsey R.; Morrissey, Samantha M.; Young, Lyndsay E.A.; Bruntz, Ronald C.; Kim, Eun J.; Wise-Mitchell, Ashley; Rizzo, Mariana Barbosa de Souza; Relich, Eric R.; Baby, Becca V.; Johnson, Lance A.; Affronti, Hayley C.; McMasters, Kelly M.; Clem, Brian F.; Gentry, Matthew S.; Yan, Jun; Wellen, Kathryn E.; Sun, Runyuan; Mitchell, Robert A.

doi:10.1126/sciadv.abi8602

Cited by 106 publications

(83 citation statements)

References 47 publications

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“…[ 78 ] M0 → M2 macrophage polarization is also accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. [ 79 ] Lactate accumulation also inhibited tumor surveillance by decreased interferon-γ in T and natural killer cells in melanomas. [ 80 ] Dendritic cells were affected in a high LDH level.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

Liu

2022

Medicine

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Background: Immune checkpoint inhibitors (ICIs) showed promising therapeutic efficacy on melanoma. Neutrophil-to-lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH) showed predictive values on prognosis of various tumors, but not on melanoma yet. This meta-analysis was conducted to investigate the prognostic role of NLR and LDH levels in melanoma treated with ICIs. Methods: A search was conducted for all reports published till March 2020 in PubMed, Web of Science, Cochrane Library, EMBASE, ClinicalTrials.gov , and the WHO International Clinical Trials Registry Platform (ICTRP). Studies were included if they investigated the association between pretreatment NLR/LDH and prognosis in melanoma patients treated with ICIs. Subgroup analysis, publication bias, and meta-regression were conducted to investigate heterogeneity. Results: A total of 6817 melanoma patients were included. Overall, high pretreatment NLR and LDH were associated with poor overall survival (OS) ( P < .001) and PFS ( P < .001). Subgroup analyses revealed that elevated NLR and LDH levels were associated with poor OS and PFS in patients treated with anti-CTLA-4 or anti-PD-1/PD-L1 alone. NLR level was superior in predicting OS if compared with LDH level in patients treated with anti-PD-1/PD-L1 + anti-CTLA-4. In subgroup analysis stratified by cutoff value, high NLR level was associated with poor OS and PFS regardless of cutoff value, but LDH works when cutoff value = upper normal limit (UNL). The predictive value of NLR and LDH levels on OS and PFS was partially compromised in the Asian populations, compared with the Western countries. Conclusion: Blood NLR and LDH levels showed great potential to be used as early prognostic biomarkers in melanoma patients treated with ICIs.

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Section: Discussionmentioning

confidence: 99%

Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

Liu

2022

Medicine

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“…LOX inactivation due to copper metabolism disorders or genetic mutations leads to the dysfunction of connective tissue ( 39 ). The enzymatic activity of ACLY has important functions in the TCA cycle ( 40 ). In addition, CDKN2A is a key gene regulating cuproptosis and has a high mutation probability in HNSCC ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

A cuproptosis and copper metabolism–related gene prognostic index for head and neck squamous cell carcinoma

Zhang

Lujin

et al. 2022

Front. Oncol.

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BackgroundThe purpose of this study was to identify the prognostic value of cuproptosis and copper metabolism–related genes, to clarify their molecular and immunological characteristics, and to elucidate their benefits in head and neck squamous cell carcinoma (HNSCC).MethodsThe details of human cuproptosis and copper metabolism–related genes were searched and filtered from the msigdb database and the latest literature. To identify prognostic genes associated with cuproptosis and copper metabolism, we used least absolute shrinkage and selection operator regression, and this coefficient was used to set up a prognostic risk score model. HNSCC samples were divided into two groups according to the median risk. Afterwards, the function and immune characteristics of these genes in HNSCC were analyzed.ResultsThe 14-gene signature was constructed to classify HNSCC patients into low-risk and high-risk groups according to the risk level. In the The Cancer Genome Atlas (TCGA) cohort, the overall survival (OS) rate of the high-risk group was lower than that of the low-risk group (P < 0.0001). The area under the curve of the time-dependent Receiver Operator Characteristic (ROC) curve assessed the good performance of the genetic signature in predicting OS and showed similar performance in the external validation cohort. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment assays and Protein-Protein Interaction (PPI) protein networks have been used to explore signaling pathways and potential mechanisms that were markedly active in patients with HNSCC. Furthermore, the 14 cuproptosis and copper metabolism-related genes were significantly correlated with the immune microenvironment, suggesting that these genes may be linked with the immune regulation and development of HNSCC.ConclusionsOur results emphasize the significance of cuproptosis and copper metabolism as a predictive biomarker for HNSCC, and its expression levels seem to be correlated with immune- related features; thus, they may be a possible biomarker for HNSCC prognosis.

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“…Tumor cells are essentially net producers of acid due to aerobic glycolysis, producing large amounts of carbon dioxide and lactic acid [ 97 ]. Lactate accumulation can be a significant TME signal to polarize M2 macrophages [ 99 ]. As tumors grow, glucose is depleted, and lactate concentrations increase.…”

Section: Energy Metabolism Of Tamsmentioning

confidence: 99%

“…As tumors grow, glucose is depleted, and lactate concentrations increase. This drives M2 macrophage reprogramming, and they need to use lactate as a source of oxidative phosphorylation, which then results in high TCA activity [ 99 ]. Even in the presence of high glucose and lactate levels, TAMs use lactate for citrate production because pyruvate generation from lactate requires fewer enzymatic processes and produces NADH [ 99 ].…”

Section: Energy Metabolism Of Tamsmentioning

confidence: 99%

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity

Hasan

Capuk

Patel

et al. 2022

Cancers

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Cancer cells possess a high metabolic demand for their rapid proliferation, survival, and progression and thus create an acidic and hypoxic tumor microenvironment (TME) deprived of nutrients. Moreover, acidity within the TME is the central regulator of tumor immunity that influences the metabolism of the immune cells and orchestrates the local and systemic immunity, thus, the TME has a major impact on tumor progression and resistance to anti-cancer therapy. Specifically, myeloid cells, which include myeloid-derived suppressor cells (MDSC), dendritic cells, and tumor-associated macrophages (TAMs), often reprogram their energy metabolism, resulting in stimulating the angiogenesis and immunosuppression of tumors. This review summarizes the recent findings of glucose, amino acids, and fatty acid metabolism changes of the tumor-associated macrophages (TAMs), and how the altered metabolism shapes the TME and anti-tumor immunity. Multiple proton pumps/transporters are involved in maintaining the alkaline intracellular pH which is necessary for the glycolytic metabolism of the myeloid cells and acidic TME. We highlighted the roles of these proteins in modulating the cellular metabolism of TAMs and their potential as therapeutic targets for improving immune checkpoint therapy.

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Lactate supports a metabolic-epigenetic link in macrophage polarization

Abstract: Macrophages use mitochondrial lactate metabolism for ACLY-dependent histone acetylation, immune suppression, and tumor progression.

Cited by 106 publications

References 47 publications

Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

A cuproptosis and copper metabolism–related gene prognostic index for head and neck squamous cell carcinoma

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity

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