Metabolic support of tumour-infiltrating regulatory T cells by lactic acid

Watson, McLane; Vignali, Paolo; Mullett, Steven J.; Overacre-Delgoffe, Abigail; Peralta, Ronal; Grebinoski, Stephanie; Menk, Ashley V.; Rittenhouse, Natalie; DePeaux, Kristin; Whetstone, Ryan D.; Vignali, Dario A.A.; Hand, Timothy W.; Poholek, Amanda C.; Morrison, Brett M.; Rothstein, Jeffrey D.; Wendell, Stacy G.; Delgoffe, Greg M.

doi:10.1038/s41586-020-03045-2

Cited by 565 publications

(514 citation statements)

References 44 publications

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“…Studies indicated that lactate could be further used by cancer cells to fuel their metabolism, drive M2 macrophage polarization (18), and severely inhibit the effector functions of cytotoxic, helper T cells (Th1/2, Tc), and natural killer cells in the TME (12,(19)(20)(21)(22). Moreover, lactate supports the metabolic need for tumor infiltrated Treg (23,24), which suppresses effector T cell functions in TME.…”

Section: Tme Uniquely Inhibits Anti-tumor Immunity Tme Is a Low Ph Environmentmentioning

confidence: 99%

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021

Front. Immunol.

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Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

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Section: Tme Uniquely Inhibits Anti-tumor Immunity Tme Is a Low Ph Environmentmentioning

confidence: 99%

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021

Front. Immunol.

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“…It is worthy of noting that many mechanisms of primary resistance to ICBs have not been completely elucidated in the field of AR. For example, gut microbiota and tumor metabolism have been acknowledged to play important roles in primary resistance to ICBs ( 157 – 159 ), while their contribution to AR is largely unknown and thus needs future exploration. The other issue in this field is that translational research is urgently needed to extend patients’ survival.…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

et al. 2021

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The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.

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“…For example, tumor cells exhibiting glycolysis can cooperate with non-glycolytic tumor cells by excreting lactate which can be taken up by the neighboring cells and metabolized via the TCA cycle [64]. The lactate excreted by glycolytic tumor cells has also been shown to support the metabolic needs of tumor-promoting regulatory T cells, and suppression of the lactate transporter MCT1 in regulatory T cells has been shown to synergize with anti-PD-1 therapy in a mouse model of melanoma [65]. Moreover, tumor cells and immune cells compete for nutrients in the tumor microenvironment and tilting the competition towards tumor-suppressive immune cells can prove to be an effective anti-tumor strategy [38,66].…”

Section: Discussionmentioning

confidence: 99%

A Mechanistic Modeling Framework Reveals the Key Principles Underlying Tumor Metabolism

Tripathi

Park²,

Pudakalakatti

et al. 2021

Preprint

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While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, utilizing glycolysis, oxidative phosphorylation, or both, and can switch between different metabolic phenotypes. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive metabolic heterogeneity. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. We report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.SignificanceThis study presents an interpretable mathematical framework for analyzing the metabolic heterogeneity and plasticity exhibited by tumor cells.

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Metabolic support of tumour-infiltrating regulatory T cells by lactic acid

Cited by 565 publications

References 44 publications

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

A Mechanistic Modeling Framework Reveals the Key Principles Underlying Tumor Metabolism

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