Resistance to Immunotherapy: A Challenge of Cancer Treatment
Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities
Abstract
Although immunotherapy plays a significant role in tumor therapy, its efficacy is impaired by an immunosuppressive tumor microenvironment. A molecule that contributes to the protumor microenvironment is the metabolic product lactate. Lactate is produced in large amounts by cancer cells in response to either hypoxia or pseudohypoxia, and its presence in excess alters the normal functioning of immune cells. A key enzyme involved in lactate metabolism is lactate dehydrogenase (LDH). Elevated baseline LDH serum levels are associated with poor outcomes of current anticancer (immune) therapies, especially in patients with melanoma. Therefore, targeting LDH and other molecules involved in lactate metabolism might improve the efficacy of immune therapies. This review summarizes current knowledge about lactate metabolism and its role in the tumor microenvironment. Based on that information, we develop a rationale for deploying drugs that target lactate metabolism in combination with immune checkpoint inhibitors to overcome lactate-mediated immune escape of tumor cells.
https://www.hindawi.com/journals/jo/2019/2084195/
Resistance to Immunotherapy: A Challenge of Cancer Treatment
Lactate at the crossroads of metabolism, inflammation, and autoimmunity
Lactate at the crossroads of metabolism, inflammation, and autoimmunity
Abstract
For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early ‘90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this “stop migration signal” is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4+ T cells to an IL‐17+ subset, and reduces the cytolytic capacity of CD8+ T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.
https://onlinelibrary.wiley.com/doi/ful ... .201646477
Abstract
For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early ‘90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this “stop migration signal” is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4+ T cells to an IL‐17+ subset, and reduces the cytolytic capacity of CD8+ T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.
https://onlinelibrary.wiley.com/doi/ful ... .201646477
Debbie
Re: Resistance to Immunotherapy: A Challenge of Cancer Treatment
Crosstalk between immunity and metabolism
The immune system is constituted of a heterogeneous population of immune cells, which are able to respond to inflammatory stimuli upon switching from a quiescent to an activated status. These responses are tightly regulated by a wide range of cell type specific receptors and transcription factors. In immune cells this determines changes in the expression of large numbers of genes and results in the acquisition of new functions, such as the production of cytokines, lipid mediators and metabolites as well as the ability to proliferate, differentiate into specialized subtypes and migrate to target tissues. All such functions require the supply of nutrients into different metabolic pathways. In the last few years there has been an increasing appreciation of how such metabolic pathways integrate with and in fact determine specific immune cell responses 1.
T-cell metabolism, inflammation, and autoimmunity
In the past few years, metabolism has been in the spotlight because of its pivotal role in disorders such as cancer as well as inflammatory and autoimmune diseases. Many studies have highlighted how cancer cells rely upon bioenergetic pathways to support their growth. As for cancer cells, immune cells also adapt their metabolic status as a consequence to changes in the external microenvironment (i.e. inflammation). T cells are key players of adaptive immunity and have high metabolic demand for their activation, proliferation, differentiation in specific cell subsets, and migration to target organs, while quiescent T cells rely mainly upon fatty acid oxidation and mitochondrial respiration to fuel their energy demand 2, 3. In response to antigens, proliferating T cells upregulate their glycolytic flux and the glucose transporter GLUT1, resulting in the biosynthesis of proteins, nucleic acids, and lipids that are essential for their activation and effector functions 4, 5. Conversely, memory T cells and/or chronically activated T cells do not proliferate and do not require high energy demand. Indeed, they mainly utilize oxidative phosphorylation (OXPHOS) to produce the required amounts of ATP 2, 3.
Effector CD4+ T cells have the ability to differentiate into Th1 (helper) cells promoting cell-mediated immunity, Th2 cells supporting the humoral immune response, Th17 cells promoting mucosal immunity, or regulatory T (Treg) cells suppressing effector T-cell function 6, 7. In contrast to Th cells, which increase glycolysis over mitochondrial metabolism, Treg cells and memory T cells display a metabolic program involving mainly lipid oxidation and OXPHOS 8. This suggests that T cells undergo metabolic reprogramming according to their differentiation state. Alterations of this fine tuning between metabolism and immunity might lead to an unbalance between pro- and anti-inflammatory responses and to the establishment of a nonresolving inflammatory environment, chronic inflammation, and autoimmunity 9.
Several studies have highlighted the molecular mechanisms that govern metabolic reprogramming in the immune system in tumors; however, their role in autoimmunity is still unclear 10. There is increasing evidence that chronically stimulated autoreactive T cells preferentially meet their metabolic demands through mitochondrial OXPHOS rather than aerobic glycolysis 8, 11. For instance, murine studies have shown that autoreactive splenocytes from lupus-prone mice preferentially convert glucose to CO2, increasing mitochondrial metabolism for ATP synthesis 12. Studies in humans also revealed that patients with autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) display defects in metabolic pathways such as glycolysis and mitochondrial oxidative metabolism 13. Indeed, clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders might involve factors, hormones, and neural mediators that link metabolism and immune system 14, 15. In this regard, the discovery of leptin, one of the most abundant adipocyte-derived hormones controlling food intake and metabolism, has suggested that an organism's nutritional status can control immune self-tolerance 16. Recently, metabolites, such as succinate, citrate and lactate, all intermediate and end products of metabolic pathways, have been shown to activate signaling, resulting in the modulation of immune functions 17-19.
The immune system is constituted of a heterogeneous population of immune cells, which are able to respond to inflammatory stimuli upon switching from a quiescent to an activated status. These responses are tightly regulated by a wide range of cell type specific receptors and transcription factors. In immune cells this determines changes in the expression of large numbers of genes and results in the acquisition of new functions, such as the production of cytokines, lipid mediators and metabolites as well as the ability to proliferate, differentiate into specialized subtypes and migrate to target tissues. All such functions require the supply of nutrients into different metabolic pathways. In the last few years there has been an increasing appreciation of how such metabolic pathways integrate with and in fact determine specific immune cell responses 1.
T-cell metabolism, inflammation, and autoimmunity
In the past few years, metabolism has been in the spotlight because of its pivotal role in disorders such as cancer as well as inflammatory and autoimmune diseases. Many studies have highlighted how cancer cells rely upon bioenergetic pathways to support their growth. As for cancer cells, immune cells also adapt their metabolic status as a consequence to changes in the external microenvironment (i.e. inflammation). T cells are key players of adaptive immunity and have high metabolic demand for their activation, proliferation, differentiation in specific cell subsets, and migration to target organs, while quiescent T cells rely mainly upon fatty acid oxidation and mitochondrial respiration to fuel their energy demand 2, 3. In response to antigens, proliferating T cells upregulate their glycolytic flux and the glucose transporter GLUT1, resulting in the biosynthesis of proteins, nucleic acids, and lipids that are essential for their activation and effector functions 4, 5. Conversely, memory T cells and/or chronically activated T cells do not proliferate and do not require high energy demand. Indeed, they mainly utilize oxidative phosphorylation (OXPHOS) to produce the required amounts of ATP 2, 3.
Effector CD4+ T cells have the ability to differentiate into Th1 (helper) cells promoting cell-mediated immunity, Th2 cells supporting the humoral immune response, Th17 cells promoting mucosal immunity, or regulatory T (Treg) cells suppressing effector T-cell function 6, 7. In contrast to Th cells, which increase glycolysis over mitochondrial metabolism, Treg cells and memory T cells display a metabolic program involving mainly lipid oxidation and OXPHOS 8. This suggests that T cells undergo metabolic reprogramming according to their differentiation state. Alterations of this fine tuning between metabolism and immunity might lead to an unbalance between pro- and anti-inflammatory responses and to the establishment of a nonresolving inflammatory environment, chronic inflammation, and autoimmunity 9.
Several studies have highlighted the molecular mechanisms that govern metabolic reprogramming in the immune system in tumors; however, their role in autoimmunity is still unclear 10. There is increasing evidence that chronically stimulated autoreactive T cells preferentially meet their metabolic demands through mitochondrial OXPHOS rather than aerobic glycolysis 8, 11. For instance, murine studies have shown that autoreactive splenocytes from lupus-prone mice preferentially convert glucose to CO2, increasing mitochondrial metabolism for ATP synthesis 12. Studies in humans also revealed that patients with autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) display defects in metabolic pathways such as glycolysis and mitochondrial oxidative metabolism 13. Indeed, clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders might involve factors, hormones, and neural mediators that link metabolism and immune system 14, 15. In this regard, the discovery of leptin, one of the most abundant adipocyte-derived hormones controlling food intake and metabolism, has suggested that an organism's nutritional status can control immune self-tolerance 16. Recently, metabolites, such as succinate, citrate and lactate, all intermediate and end products of metabolic pathways, have been shown to activate signaling, resulting in the modulation of immune functions 17-19.
The function of adaptive immune responses is to destroy invading pathogens and any toxic molecules they produce. Because these responses are destructive, it is crucial that they be made only in response to molecules that are foreign to the host and not to the molecules of the host itself.
Debbie