Lactate as a Regulator of Cancer Inflammation and Immunity

Santos, Nuno; Pereira-Nunes, Andreia; Baltazar, Fátima; Granja, Sara

doi:10.20900/immunometab20190015

Cited by 16 publications

(12 citation statements)

References 99 publications

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“…Loss of the p53 protein prevents expression of the synthesis of cytochrome c oxidase (SCO2) gene, decreasing mitochondrial respiration (36). Lactate can also function as a paracrine tumor molecule (37). Acidosis often precedes angiogenesis and lactate can stimulate HIF expression independently of hypoxia (38).…”

Section: Oncogenic Triggers Of Glycolytic Metabolismmentioning

confidence: 99%

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

et al. 2020

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To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.

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Section: Oncogenic Triggers Of Glycolytic Metabolismmentioning

confidence: 99%

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

et al. 2020

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“…Lactate is elevated in inflammatory diseases due to increased production or impaired clearance, which then influences immune cell function. Several recent reviews have discussed the role of lactate in immune cell activation within one specific disease context ( Pucino et al, 2017 ; Brooks, 2018 ; Santos et al, 2019 ; Baltazar et al, 2020 ; Ivashkiv, 2020 ). Thus in the current work, we have reviewed multiple cell types and disease models to help shape our overall understanding of how lactate influences immune cell function.…”

Section: Introductionmentioning

confidence: 99%

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

et al. 2021

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Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.

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“…Blocking tumor metabolites pharmacologically is also an exciting approach that might help to prevent inhibition of adoptively transferred T cells and rescue the endogenous immune response against tumor cells. Alterations of the tumor milieu to produce less lactate and acidosis, or conditions that buffer acidity are investigated and show recovery of immune cell function as well as improved therapeutic effects of anti-PD-1 treatments (40,42,43,58,(62)(63)(64)(65)(66)(67).…”

Section: Discussion and Relevance For Immunotherapymentioning

confidence: 99%

Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

et al. 2020

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Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy.

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Lactate as a Regulator of Cancer Inflammation and Immunity

Cited by 16 publications

References 99 publications

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

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