Determinants of Tissue-Specific Metabolic Adaptation of T Cells

Varanasi, Siva Karthik; Kumar, Sushmitha Vijaya; Rouse, Barry T.

doi:10.1016/j.cmet.2020.10.013

Cited by 34 publications

(20 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although drug targeting of metabolism in immune cells (Table 1) is not covered here, it is an emerging area that holds additional hope for new cancer metabolic drugs. As such, fundamental research to provide a deeper understanding of how metabolic drugs affect the TIME, particularly immune cells, is necessary to enable precision oncology [221][222][223] .…”

Section: Targeting Time-associated Metabolismmentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

View full text Add to dashboard Cite

Before Sidney Farber published his seminal paper in 1948 in The New England Journal of Medicine describing anti-folate-induced remissions 1 , childhood acute lymphocytic leukaemia (ALL) was universally fatal. Thirty years before this article was published, Otto Warburg's determination to conquer cancer led him to discover that many tumours used aerobic glycolysis (also known as the Warburg effect) to convert almost all glucose to lactate even in the presence of oxygen 2 . Aerobic glycolysis, however, has never been successfully exploited clinically, particularly as the use of 2-deoxyglucose, which inhibits glycolysis, was proved to have undesirable side effects and limited efficacy in humans 3 . Farber noted the clinical 'accelerated phenomenon' among 11 children treated with an active form of folate, pteroyltriglutamic acid, which was thought to have broad anticancer activity, and thus sought folate antagonists as therapeutic agents. Working with chemist Yellapragada Subbarow, the anti-folate aminopterin was synthesized, and Farber was able to induce remissions in children with ALL, thus providing the foundation for cancer chemotherapy 4 . Today, another folate antagonist, methotrexate, is still used in the multi-chemotherapy treatment of childhood ALL and, used together with l-asparaginase, induces a remarkable 90% cure rate. Indeed, many anti-metabolite drugs, particularly those targeting nucleotide metabolism, have been approved and used in the clinic (Table 1). The recent approval of drugs that target mutant isocitrate dehydrogenases in acute myeloid leukaemias (AMLs) (Table 1) provides a milestone in targeting cancer metabolism with precision and establishes that metabolic therapy can be highly effective.Warburg's and Farber's ideas were conceptually displaced in the 1980s as oncogenes and tumour suppressors became recognized as targets in human cancer treatments. Molecular biology took centre stage, and the drive to target oncogenes began with vigour, resulting in many effective anticancer kinase drugs that displaced interest in targeting metabolism. However, the links between oncogenes, tumour suppressors and metabolism began to emerge in the 1990s, ushering in a resurgence of interest in cancer metabolism [5][6][7] . More recently, the success of immunotherapy underscores the importance of non-cancer-cell autonomous components of the tumour immune microenvironment (TIME) [8][9][10] , which is a neoplastic hub of metabolically active cells comprising tumour cells, immune cells, stromal cells and blood and lymph vessel cells, all of which are involved in tumour growth. In this regard, targeting cancer metabolism must be based on a thorough understanding of how inhibiting specific metabolic pathways affects the TIME cells, which can either dampen or promote tumour progression. In this Review, we cover the fundamentals of cancer metabolism and focus on recent small-molecule drug discovery efforts to target cancer.

show abstract

Section: Targeting Time-associated Metabolismmentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

View full text Add to dashboard Cite

show abstract

“…CD8 + T cells is a cytotoxic T lymphocyte that secretes various cytokines (granzymes, perforin, etc.) to participate in the immune function (29)(30)(31). Several studies (32)(33)(34)(35) have found the elevated expression of the CD8 + T cells in lung tissue, bronchoalveolar lavage fluid or induced sputum of patients with COPD.…”

Section: Discussionmentioning

confidence: 99%

Identification of Inflammation-Related Biomarker Lp-PLA2 for Patients With COPD by Comprehensive Analysis

et al. 2021

View full text Add to dashboard Cite

PurposeChronic obstructive pulmonary disease (COPD) is a complex and persistent lung disease and lack of biomarkers. The aim of this study is to screen and verify effective biomarkers for medical practice.MethodsDifferential expressed genes analysis and weighted co-expression network analysis were used to explore potential biomarker. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene set enrichment analysis (GSEA) analysis were used to explore potential mechanism. CIBERSORTx website was used to evaluate tissue-infiltrating immune cells. Enzyme-linked immunosorbent assay (ELISA) was used to assess the concentrations of the Lp-PLA2 in serum.ResultsTen genes were selected via combined DEGs and WGCNA. Furthermore, PLA2G7 was choose based on validation from independent datasets. Immune infiltrate and enrichment analysis suggest PLA2G7 may regulate immune pathway via macrophages. Next, Lp-PLA2(coded by PLA2G7 gene) level was upregulated in COPD patients, increased along with The Global Average of COPD (GOLD) stage. In additional, Lp-PLA2 level was significant correlate with FEV1/FVC, BMI, FFMI, CAT score, mMRC score and 6MWD of COPD patients. Finally, the predictive efficiency of Lp-PLA2 level (AUC:0.796) and derived nomogram model (AUC:0.884) in exercise tolerance was notably superior to that of the sit-to-stand test and traditional clinical features.ConclusionLp-PLA2 is a promising biomarker for COPD patients and is suitable for assessing exercise tolerance in clinical practice.

show abstract

“…Oxidative phosphorylation provides most of the energy for primitive and memory CD8 T cells (Vardhana et al, 2020). However, the increase of glycolysis is a prerequisite for the growth and activation of CD8 T cells (Varanasi et al, 2020). Loss of phosphatase and tension homolog (PTEN) in T cells leads to dysregulation of immune homeostasis (Lin et al, 2021).…”

Section: Non-kinase Function Of Agkmentioning

confidence: 99%

Acylglycerol Kinase-Targeted Therapies in Oncology

Chu

Hong

Zheng

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Acylglycerol kinase (AGK) is a recently discovered mitochondrial lipid kinase, and mutation of its gene is the fundamental cause of Sengers syndrome. AGK is not only involved in the stability of lipid metabolism but also closely related to mitochondrial protein transport, glycolysis, and thrombocytopoiesis. Evidence indicates that AGK is an important factor in the occurrence and development of tumors. Specifically, AGK has been identified as an oncogene that partakes in the regulation of tumor cell growth, invasion, metastasis, and drug resistance. The versatility of AGK and its unique role in different types of cancerous and normal cells greatly piqued our interest. We believe that AGK is a promising target for cancer therapy. Therefore, this review summarizes the main research advances concerning AGK, including the discovery of its physiological/pathogenic mechanisms, and provides a reference for the feasible evaluation of AGK as a therapeutic target for human diseases, particularly tumors.

show abstract

Determinants of Tissue-Specific Metabolic Adaptation of T Cells

Cited by 34 publications

References 96 publications

Targeting cancer metabolism in the era of precision oncology

Targeting cancer metabolism in the era of precision oncology

Identification of Inflammation-Related Biomarker Lp-PLA2 for Patients With COPD by Comprehensive Analysis

Acylglycerol Kinase-Targeted Therapies in Oncology

Contact Info

Product

Resources

About