Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition

Ecker, Christopher; Riley, James L.

doi:10.1016/j.cmet.2018.07.009

Cited by 20 publications

(16 citation statements)

References 62 publications

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“…Intriguingly, depletion of myeloid cells capable of degrading arginine and tryptophan from PDAC tumors resulted in increased T cell infiltration, proliferation, and activation in PDAC tumors (Bayne et al, 2012; Stromnes et al, 2014; Zhang et al, 2017). Future studies determining how T cell metabolism and function is impacted by tumor nutrient levels could yield insight into how tumors suppress immune rejection (Ecker and Riley, 2018).…”

Section: Discussionmentioning

confidence: 99%

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Sullivan

Danai

Lewis

et al. 2019

eLife

434

395

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Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

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Section: Discussionmentioning

confidence: 99%

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Sullivan

Danai

Lewis

et al. 2019

eLife

434

395

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“…With the gene expression profiles of single cells from tumors, we were able to identify metabolic features that distinguish subpopulations of immune and stromal cells. This approach has the advantage of providing a direct snapshot of the metabolic landscape of tumors and their microenvironment consisting of numerous known and unknown types of cells whose metabolism is greatly influenced by the interactions between them and the shortage of nutrients in the tumor microenvironment 11,58,59 . We found that some non-malignant cell subpopulations, Ths and Tregs for instance, adopt metabolic phenotypes distinct from what they show in ex vivo culture conditions 38 .…”

Section: Discussionmentioning

confidence: 99%

Metabolic landscape of the tumor microenvironment at single cell resolution

2019

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The tumor milieu consists of numerous cell types each existing in a different environment. However, a characterization of metabolic heterogeneity at single-cell resolution is not established. Here, we develop a computational pipeline to study metabolic programs in single cells. In two representative human cancers, melanoma and head and neck, we apply this algorithm to define the intratumor metabolic landscape. We report an overall discordance between analyses of single cells and those of bulk tumors with higher metabolic activity in malignant cells than previously appreciated. Variation in mitochondrial programs is found to be the major contributor to metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of the tumor microenvironment.

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“…Several recent reports indicate that the metabolic rewiring of tumors interferes with antitumor immunity in many ways (reviewed by ref. 37). On one hand, tumor-derived metabolites, such as lactate or adenosine, influence the immune response.…”

Section: Discussionmentioning

confidence: 99%

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Püschel

Favaro

Redondo-Pedraza

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

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Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition

Abstract: Reductionist in vitro T cell assays have identified metabolic pathways critical for T cell function within the tumor microenvironment. We discuss the challenges of testing these concepts using in vivo tumor models.

Cited by 20 publications

References 62 publications

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Metabolic landscape of the tumor microenvironment at single cell resolution

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

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