Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma

Ottensmeier, Christian; Perry, Kate L.; Harden, Elena L.; Stasakova, Jana; Jenei, Veronika; Fleming, Jason C.; Wood, Oliver; Woo, Jeongmin; Woelk, Christopher H.; Thomas, Gareth J.; Thirdborough, Stephen M.

doi:10.1158/0008-5472.can-15-3121

Cited by 88 publications

(75 citation statements)

References 48 publications

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“…This effect is mediated by the absence of the glycolytic product phosphoenolpyruvate, which sustains Ca 2+ and NFAT by blocking sarco/endoplasmic reticulum Ca 2+ -ATPase (Ho et al, 2015). In line with this, our group observed a negative correlation between accelerated tumoral glucose metabolism and T-cell infiltration in renal cell carcinoma (Singer et al, 2011), with similar observations made in oral squamous cell carcinoma (Ottensmeier et al, 2016). Interestingly, emerging clinical data point towards tumor glucose metabolism as a mechanism of resistance to T-cell-mediated tumor rejection.…”

Section: Tumors Modulate Local Concentrations Of Nutrients That Are Csupporting

confidence: 85%

Immunometabolism in cancer at a glance

Singer

Cheng

Kreutz

et al. 2018

Disease Models &Amp; Mechanisms

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The scientific knowledge about tumor metabolism has grown at a fascinating rate in recent decades. We now know that tumors are highly active both in their metabolism of available nutrients and in the secretion of metabolic by-products. However, cancer cells can modulate metabolic pathways and thus adapt to specific nutrients. Unlike tumor cells, immune cells are not subject to a ‘micro-evolution’ that would allow them to adapt to progressing tumors that continuously develop new mechanisms of immune escape. Consequently, immune cells are often irreversibly affected and may allow or even support cancer progression. The mechanisms of how tumors change immune cell function are not sufficiently explored. It is, however, clear that commonly shared features of tumor metabolism, such as local nutrient depletion or production of metabolic ‘waste’ can broadly affect immune cells and contribute to immune evasion. Moreover, immune cells utilize different metabolic programs based on their subtype and function, and these immunometabolic pathways can be modified in the tumor microenvironment. In this review and accompanying poster, we identify and describe the common mechanisms by which tumors metabolically affect the tumor-infiltrating cells of native and adaptive immunity, and discuss how these mechanisms may lead to novel therapeutic opportunities.

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Section: Tumors Modulate Local Concentrations Of Nutrients That Are Csupporting

confidence: 85%

Immunometabolism in cancer at a glance

Singer

Cheng

Kreutz

et al. 2018

Disease Models &Amp; Mechanisms

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“…As tumor cells can express more nutrient import molecules than activated T cells, tumor cells commonly outcompete immune cells for glucose. Indeed, overexpression of GLUT1 in cancer cells correlates with low CD8 T cell infiltration in renal cell carcinoma (Singer et al, 2011) and SCC (Ottensmeier et al, 2016), and poor patient prognosis in melanoma (Su et al, 2016), PDA (Davis-Yadley et al, 2016; Lu et al, 2016) and ovarian cancer (Cho et al, 2013). Successful competition for glucose by tumor cells facilitates the capacities to simultaneously maintain high metabolic and proliferative rates while suppressing anti-tumor immunity.…”

Section: Metabolic Challenges In the Tme: Impact On T Lymphocytes Andmentioning

confidence: 99%

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

2017

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T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

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“…High lactate levels inhibited proliferation and cytokine production in human cytotoxic lymphocytes, which was attributed to disruption of a required lactate gradient, prevention of lactate export, and metabolic perturbation[94]. Additionally, in squamous tumors, highly glycolytic tumors had reduced CD8+ T cell infiltration[95]. …”

Section: Tumor Infiltrating Lymphocytes and Metabolic Adaptationmentioning

confidence: 99%

Nutrients and the microenvironment to feed a T cell army

Johnson

Siska

Contreras

et al. 2016

Seminars in Immunology

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T cells have dramatic functional and proliferative shifts in the course of maintaining immune protection from pathogens and cancer. To support these changes, T cells undergo metabolic reprogramming upon stimulation and again after antigen clearance. Depending on the extrinsic cell signals, T cells can differentiate into functionally distinct subsets that utilize and require diverse metabolic programs. Effector T cells (Teff) enhance glucose and glutamine uptake, whereas regulatory T cells (Treg) do not rely on significant rates of glycolysis. The dependence of these subsets on specific metabolic programs makes T cells reliant on these signaling pathways and nutrients. Metabolic pathways, such as those regulated by mTOR and Myc, augment T cell glycolysis and glutaminolysis programs to promote T cell activity. These pathways respond to signals and control metabolism through both transcriptional or post-transcriptional mechanisms. Epigenetic modifications also play an important role by stabilizing the transcription factors that define subset specific reprogramming. In addition, circadian rhythm cycling may also influence energy use, immune surveillance, and function of T cells. In this review, we focus on the metabolic and nutrient requirements of T cells, and how canonical pathways of growth and metabolism regulate nutrients that are essential for T cell function.

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Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma

Cited by 88 publications

References 48 publications

Immunometabolism in cancer at a glance

Immunometabolism in cancer at a glance

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Nutrients and the microenvironment to feed a T cell army

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