Metabolic interventions in the immune response to cancer

O’Sullivan, David; Sanin, David E.; Pearce, Edward J.; Pearce, Erika L.

doi:10.1038/s41577-019-0140-9

Cited by 202 publications

(165 citation statements)

References 165 publications

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“…Cancer cells metabolize glucose more rapidly compared to normal cells, producing large amounts of lactate, in a process known as the Warburg effect (323). This metabolic shift has important ramifications on the TME, and thus, on tumorinfiltrating immune cells (324). One metabolite that is present at higher concentrations in the TME is adenosine.…”

Section: Modulating Tumor Metabolitesmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Modulating Tumor Metabolitesmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…These differences cause difficulties in diagnostic . The level of metabolite released from each cell is the indicator of an abnormality . Real‐time monitoring of a signaling molecule released from the living cells could improve the understanding of a targeted disease and new therapeutic and diagnostic approaches.…”

Section: Figurementioning

confidence: 99%

Monitoring H₂O₂ on the Surface of Single Cells with Liquid Crystal Elastomer Microspheres

Khan

et al. 2020

Angew Chem Int Ed

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Live‐imaging of signaling molecules released from living cells is a fundamental challenge in life sciences. Herein, we synthesized liquid crystal elastomer microspheres functionalized with horse‐radish peroxidase (LCEM‐HRP), which can be immobilized directly on the cell membrane to monitor real‐time release of H2O2 at the single‐cell level. LCEM‐HRP could report H2O2 through a concentric‐to‐radial (C‐R) transfiguration, which is due to the deprotonation of LCEM‐HRP and the break of inter or intra‐chain hydrogen bonding in LCEM‐HRP caused by HRP‐catalyzed reduction of H2O2. The level of transfiguration of LCEM‐HRP revealed the different amounts of H2O2 released from cells. The estimated detection sensitivity was ≈2.2×10−7 μm for 10 min of detection time. The cell lines and cell–cell heterogeneity was explored from different configurations. LCEM‐HRP presents a new approach for in situ real‐time imaging of H2O2 release from living cells and can be the basis for seeking more advanced chemical probes for imaging of various signaling molecules in the cellular microenvironment.

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“…In addition to lineage intrinsic factors, cell activation and tissue of residence, a cell's metabolism is influenced by its location within a specific tissue microenvironment and its interactions with neighboring cells 3,28 , together critically shaping immune responses against cancer 26,27 . The antibody-based nature of scMEP enabled us to directly transfer this approach to the recently-developed multiplexed ion beam imaging (MIBI-TOF) platform 32 , thus allowing multimodal, high-dimensional, image-based analysis of the cellular metabolic regulome, phenotypic state, and importantly, cellular interactions and localizations within the tissue microenvironment.…”

Section: Cellular Metabolism Is Related To Spatial Organization In Humentioning

confidence: 99%

“…Furthermore, given the recently highlighted significant metabolic differences between physiologically activated cells and in vitro models 25 , there is a need to validate and more directly analyze metabolic states directly ex vivo. Especially analysis of limited samples from human clinical material could determine tissue-specific metabolic states as well as their potential modulation in human diseases, particularly cancer 26,27 . Moreover, multimodal analysis of metabolic immune cell states within their physiological microenvironment 3,28 or in metabolically challenging contexts such as cancer could reveal novel therapeutic targets and guide clinical decisions 29,30 .…”

Section: Introductionmentioning

confidence: 99%

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

Hartmann

Mrdjen

McCaffrey

et al. 2020

Preprint

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Cellular metabolism regulates immune cell activation, differentiation and effector functions to the extent that its perturbation can augment immune responses. However, the analytical technologies available to study cellular metabolism lack single-cell resolution, obscuring metabolic heterogeneity and its connection to immune phenotype and function. To that end, we utilized high-dimensional, antibody-based technologies to simultaneously quantify the single-cell metabolic regulome in combination with phenotypic identity. Mass cytometry (CyTOF)-based application of this approach to early human T cell activation enabled the comprehensive reconstruction of the coordinated metabolic remodeling of naïve CD8 + T cells and aligned with conventional bulk assays for glycolysis and oxidative phosphorylation. Extending this analysis to a variety of tissue-resident immune cells revealed tissue-restricted metabolic states of human cytotoxic T cells, including metabolically repressed subsets that expressed CD39 and PD1 and that were enriched in colorectal carcinoma versus healthy adjacent tissue. Finally, combining this approach with multiplexed ion beam imaging by time-of-flight (MIBI-TOF) demonstrated the existence of spatially enriched metabolic neighborhoods, independent of cell identity and additionally revealed exclusion of metabolically repressed cytotoxic T cell states from the tumor-immune boundary in human colorectal carcinoma. Overall, we provide an approach that permits the robust approximation of metabolic states in individual cells along with multimodal analysis of cell identity and functional characteristics that can be applied to human clinical samples to study cellular metabolism how it may be perturbed to affect immunological outcomes.

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Metabolic interventions in the immune response to cancer

Cited by 202 publications

References 165 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Monitoring H₂O₂ on the Surface of Single Cells with Liquid Crystal Elastomer Microspheres

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

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Metabolic interventions in the immune response to cancer

Cited by 202 publications

References 165 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Monitoring H2O2 on the Surface of Single Cells with Liquid Crystal Elastomer Microspheres

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

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Product

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Monitoring H₂O₂ on the Surface of Single Cells with Liquid Crystal Elastomer Microspheres