Metabolic Instruction of Immunity

Buck, Michael D.; Sowell, Ryan; Kaech, Susan M.; Pearce, Erika L.

doi:10.1016/j.cell.2017.04.004

Cited by 901 publications

(846 citation statements)

References 155 publications

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“…We demonstrate that metabolites induced in this environment have the capacity to affect both antibiotic efficacy and immune function and that the direct consequences of antibiotics on the metabolism of immune cells can inhibit their phagocytic activity. These data highlight the complex interactions elicited by antibiotics at the site of infection and support prior in vitro studies demonstrating that the host metabolic environment is critical for the function of both antibiotics (Yang et al, 2017) and immune cells (Buck et al, 2017). …”

Section: Discussionsupporting

confidence: 81%

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Yang

Bhargava

McCloskey

et al. 2017

Cell Host & Microbe

199

160

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SUMMARY Bactericidal antibiotics alter microbial metabolism as part of their lethality and can damage mitochondria in mammalian cells. In addition, antibiotic susceptibility is sensitive to extracellular metabolites, but it remains unknown if metabolites present at an infection site can affect either treatment efficacy or immune function. Here, we quantify local metabolic changes in the host microenvironment following antibiotic treatment for a peritoneal Escherichia coli infection. Antibiotic treatment elicits microbiome-independent changes in local metabolites but not those distal to the infection site by acting directly on host cells. The metabolites induced during treatment, such as AMP, reduce antibiotic efficacy and enhance phagocytic killing. Moreover, antibiotic treatment impairs immune function by inhibiting respiratory activity in immune cells. Collectively, these results highlight the immunomodulatory potential of antibiotics and reveal the local metabolic microenvironment to be an important determinant of infection resolution.

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Section: Discussionsupporting

confidence: 81%

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Yang

Bhargava

McCloskey

et al. 2017

Cell Host & Microbe

199

160

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“…Additionally, immunotherapies are playing an increasing role in cancer therapy, and immune cell fate can also be influenced by metabolism. Determining how immune cell metabolism interacts with tumor metabolism, and how this is modulated by drugs targeting metabolic enzymes, might aid in the design of more effective immunotherapies (Buck et al, 2017; Mockler et al, 2014). …”

Section: What Dictates Metabolic Dependencies?mentioning

confidence: 99%

Targeting Metabolism for Cancer Therapy

Luengo

Gui

Heiden

2017

Cell Chemical Biology

733

624

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Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in pre-clinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.

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“…The TME is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone-marrow-derived inflammatory cells, lymphocytes, signaling molecules and the extracellular matrix [6,7]. Metabolites and recently highlighted factors regulating tumor-TME cell interaction are important elements in the TME [1,8].…”

Section: Original Papermentioning

confidence: 99%

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Wang

Senyan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lactate is one of the products of glycolysis and is a hallmark of the Warburg effect. Glycolysis is found in tumor as well as immune cells. However, the effects of lactate on the function of tumor-infiltrating T cells (TILs) are rarely reported. Methods: In the present study, we investigated lactate and other glycolysis-related metabolites within TILs of human gastric cancer (GC). Lactate concentration was determined by liquid chromatography–mass spectrometry. The functional effects and clinical relevance of excessive lactate on T cells were investigated in clinical samples, and the mechanism of increased lactate was explored. Results: Lactate was significantly increased in GC TILs and related to decreased T helper (Th)1 cells and cytotoxic T lymphocytes (CTLs). Increased lactate within GC TILs was positively correlated with increased lactate dehydrogenase A (LDH)A. Expression of LDHA in GC TILs was also negatively correlated with percentages of Th1 cells and CTLs. Decreased miR-34a expression in GC TILs was responsible for increased expression of LDHA. A hypoxic tumor environment was responsible for decreased miR-34a and lactate-induced impaired immune function. Conclusion: We found that hypoxia decreases miR-34a expression and lose miR-34a regulation on LDHA, thus increasing lactate level within GC TILs and impairing immune function in GC.

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Metabolic Instruction of Immunity

Cited by 901 publications

References 155 publications

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Targeting Metabolism for Cancer Therapy

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

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