Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer

Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.Subject terms: Cancer, Mechanisms of disease     

Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients. A deeper understanding of how metabolic reprogramming in the tumor microenvironment(TME) regulates immunity remains a major challenge to tumor eradication. It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function. Tumor cells compete with infiltrating immune cells for nutrients and metabolites. Notably, the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function, and elevated inhibitory signals may favor cancer immune evasion. The major energy sources that supply different immune cell subtypes also undergo reprogramming. We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies. In this context, targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.     

CD8+ T cell metabolic changes in breast cancer

Immunometabolism has advanced our understanding of how the cellular environment and nutrient availability regulates immune cell fate. Not only are metabolic pathways closely tied to cell signaling and differentiation, but can induce different subsets of immune cells to adopt unique metabolic programs, influencing disease progression. Dysregulation of immune cell metabolism plays an essential role in the progression of several diseases including breast cancer (BC). Metabolic reprogramming plays a critical role in regulating T cell functions. CD8⁺ T cells are an essential cell type within the tumor microenvironment (TME). To induce antitumor responses, CD8⁺ T cells need to adapt their metabolism to fulfill their energy requirement for effective function. However, different markers and immunologic techniques have made identifying specific CD8⁺ T cells subtypes in BC a challenge to the field. This review discusses the immunometabolic processes of CD8⁺ T cell in the TME in the context of BC and highlights the role of CD8⁺ T cell metabolic changes in tumor progression.     

Ionizing Radiation Impairs T Cell Activation by Affecting Metabolic Reprogramming

Ionizing radiation has a variety of acute and long-lasting adverse effects on the immune system. Whereas measureable effects of radiation on immune cell cytotoxicity and population change have been well studied in human and animal models, little is known about the functional alterations of the surviving immune cells after ionizing radiation. The objective of this study was to delineate the effects of radiation on T cell function by studying the alterations of T cell receptor activation and metabolic changes in activated T cells isolated from previously irradiated animals. Using a global metabolomics profiling approach, for the first time we demonstrate that ionizing radiation impairs metabolic reprogramming of T cell activation, which leads to substantial decreases in the efficiency of key metabolic processes required for activation, such as glucose uptake, glycolysis, and energy metabolism. In-depth understanding of how radiation impacts T cell function highlighting modulation of metabolism during activation is not only a novel approach to investigate the pivotal processes in the shift of T cell homeostasis after radiation, it also may lead to new targets for therapeutic manipulation in the combination of radiotherapy and immune therapy. Given that appreciable effects were observed with as low as 10 cGy, our results also have implications for low dose environmental exposures.     

The murine Kupffer cell. II. Accessory cell function in in vitro primary antibody responses, mitogen-induced proliferation, and stimulation of mixed lymphocyte responses

The ability of murine Kupffer cells to function in several in vitro immunologic systems was investigated. These cells have been shown previously to function as accessory cells in antigen-stimulated T cell proliferation in response to protein antigens. In the present study it has been demonstrated that murine Kupffer cells also are competent as accessory cells in in vitro primary antibody responses to TNP-KLH and for T cell proliferative responses to concanavalin A. In addition, murine Kupffer cells were found to be potent stimulators of mixed lymphocyte responses. These studies extend previous observations by demonstrating that Kupffer cells are competent accessory cells in several distinct in vitro correlates of in vivo immune responses. The role of Kupffer cells in in vivo immune responses, particularly those to enterically derived antigens, may require re-evaluation in the light of these findings.     

How Mitochondrial Metabolism Contributes to Macrophage Phenotype and Functions

Metabolic reprogramming of cells from the innate immune system is one of the most noteworthy topics in immunological research nowadays. Upon infection or tissue damage, innate immune cells, such as macrophages, mobilize various immune and metabolic signals to mount a response best suited to eradicate the threat. Current data indicate that both the immune and metabolic responses are closely interconnected. On account of its peculiar position in regulating both of these processes, the mitochondrion has emerged as a critical organelle that orchestrates the coordinated metabolic and immune adaptations in macrophages. Significant effort is now underway to understand how metabolic features of differentiated macrophages regulate their immune specificities with the eventual goal to manipulate cellular metabolism to control immunity. In this review, we highlight some of the recent work that place cellular and mitochondrial metabolism in a central position in the macrophage differentiation program.     

The invertebrate midintestinal gland (“hepatopancreas”) is an evolutionary forerunner in the integration of immunity and metabolism

The immune system has an impact on the metabolic performance in vertebrates, thus the metabolic effects of immune cells are receiving intense attention today in the biomedical field. However, the evolutionary origin of the immunity–metabolism interaction is still uncertain. In this review, I show that mollusks and crustaceans integrate immune functions to a metabolic organ, the midintestinal gland (“hepatopancreas”). In these animals, the epithelial cells of the midintestinal gland are major sources of immune molecules, such as lectins, hemocyanin, ferritin, antibacterial and antiviral proteins, proteolytic enzymes and nitric oxide. There is crosstalk between midintestinal gland cells and phagocytes, which aids the initiation of the immune response and the clearance of pathogens. The midintestinal gland is thereby an integrated organ of immunity and metabolism. It is likely that immunity was the primary function of the midintestinal gland cells and that their role in the intermediate metabolism has evolved during the course of their further specialization.     

Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease

Many aspects of the cell biology of lymphocytes, macrophages, and neutrophils have been studied extensively. Our recent work on these cells has investigated how fuel metabolism, especially glutamine metabolism, is related to the specific function of these cells in the inflammatory response. The high rate of glutamine utilization and its metabolism in such immune cells has raised the question of why glutamine is responsible for these functions. The macrophage has access to a variety of metabolic fuels both in vivo and in vitro. The quantitatively important role of glutamine in the processes of free radical and cytokine production has been established in our laboratories. Our current understanding of the rate of utilization and the pathway of metabolism of glutamine by cells of the immune system raises some intriguing questions concerning therapeutic manipulation of utilization of this amino acid, specifically the phagocytic and secretory capacities of cells of the defense system can be beneficially altered.     

Glutamine regulates mitochondrial uncoupling protein 2 to promote glutaminolysis in neuroblastoma cells

Mitochondrial uncoupling protein 2 (UCP2) is highly abundant in rapidly proliferating cells that utilize aerobic glycolysis, such as stem cells, cancer cells, and cells of the immune system. However, the function of UCP2 has been a longstanding conundrum. Considering the strict regulation and unusually short life time of the protein, we propose that UCP2 acts as a “signaling protein” under nutrient shortage in cancer cells. We reveal that glutamine shortage induces the rapid and reversible downregulation of UCP2, decrease of the metabolic activity and proliferation of neuroblastoma cells, that are regulated by glutamine per se but not by glutamine metabolism. Our findings indicate a very rapid (within 1?h) metabolic adaptation that allows the cell to survive by either shifting its metabolism to the use of the alternative fuel glutamine or going into a reversible, more quiescent state. The results imply that UCP2 facilitates glutamine utilization as an energetic fuel source, thereby providing metabolic flexibility during glucose shortage. The targeting UCP2 by drugs to intervene with cancer cell metabolism may represent a new strategy for treatment of cancers resistant to other therapies.     

Sphingolipids and the balancing of immune cell function: lessons from the mast cell

Recent studies reveal that metabolites of sphingomyelin are critically important for initiation and maintenance of diverse aspects of immune cell activation and function. The conversion of sphingomyelin to ceramide, sphingosine, or sphingosine-1-phosphate (S1P) provides interconvertible metabolites with distinct biological activities. Whereas ceramide and sphingosine function to induce apoptosis and to dampen mast cell responsiveness, S1P functions as a chemoattractant and can up-regulate some effector responses. Many of the S1P effects are mediated through S1P receptor family members (S1P(1-5)). S1P(1), which is required for thymocyte emigration and lymphocyte recirculation, is also essential for Ag-induced mast cell chemotaxis, whereas S1P(2) is important for mast cell degranulation. S1P is released to the extracellular milieu by Ag-stimulated mast cells, enhancing inflammatory cell functions. Modulation of S1P receptor expression profiles, and of enzymes involved in sphingolipid metabolism, particularly sphingosine kinases, are key in balancing mast cell and immune cell responses. Current efforts are unraveling the complex underlying mechanisms regulating the sphingolipid pathway. Pharmacological intervention of these key processes may hold promise for controlling unwanted immune responses.     

Regulation of immune responses by L-arginine metabolism

L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.     

Listeria monocytogenes cytosolic metabolism promotes replication,survival, and evasion of innate immunity

Listeria monocytogenes, the causative agent of listeriosis, is an intracellular pathogen that is exquisitely evolved to survive and replicate in the cytosol of eukaryotic cells. Eukaryotic cells typically restrict bacteria from colonising the cytosol, likely through a combination of cell autonomous defences, nutritional immunity, and innate immune responses including induction of programmed cell death. This suggests that L. monocytogenes and other professional cytosolic pathogens possess unique metabolic adaptations, not only to support replication but also to facilitate resistance to host‐derived stresses/defences and avoidance of innate immune activation. In this review, we outline our current understanding of L. monocytogenes metabolism in the host cytosol and highlight major metabolic processes which promote intracellular replication and survival.     

The interplay between central metabolism and innate immune responses

A growing body of recent studies bring into light an important cross-talk between immune response and metabolism not only at the level of the organism as a whole, but also at the level of the individual cells. Cellular bioenergetics functions not only as a power plant to fuel up the cells, but the intermediate metabolites are shown to play an important role to modulate cellular responses. It is especially the pathways through which a cell metabolizes glucose that have been recently shown to influence both innate and adaptive immune responses, with oxidative phosphorylation used by resting or tolerant cells, while aerobic glycolysis (also termed ‘Warburg effect’) fueling activated cells. In this review we will address how the center metabolism shifts upon activation in the innate immune cells and how the intermediate metabolites modulate the function of immune cells.     

Endothelial cell metabolism in health and disease: impact of hypoxia

In contrast to the general belief, endothelial cell (EC) metabolism has recently been identified as a driver rather than a bystander effect of angiogenesis in health and disease. Indeed, different EC subtypes present with distinct metabolic properties, which determine their function in angiogenesis upon growth factor stimulation. One of the main stimulators of angiogenesis is hypoxia, frequently observed in disease settings such as cancer and atherosclerosis. It has long been established that hypoxic signalling and metabolism changes are highly interlinked. In this review, we will provide an overview of the literature and recent findings on hypoxia‐driven EC function and metabolism in health and disease. We summarize evidence on metabolic crosstalk between different hypoxic cell types with ECs and suggest new metabolic targets.     

Diacylglycerol kinase ζ: at the crossroads of lipid signaling and protein complex organization

Diacylglycerol (DAG) and phosphatidic acid (PA) are lipids with unique functions as metabolic intermediates, basic membrane constituents, and second-signal components. Diacylglycerol kinases (DGK) regulate the levels of these two lipids, catalyzing the interconversion of one to the other. The DGK family of enzymes is composed of 10 isoforms, grouped into five subfamilies based on the presence of distinct regulatory domains. From its initial characterization as a type IV DGK to the generation of mouse models showing its importance in cardiac dysfunction and immune pathologies, diacylglycerol kinase ζ (DGKζ) has proved an excellent example of the critical role of lipid-metabolizing enzymes in the control of cell responses. Although the mechanism that regulates this enzyme is not well known, many studies demonstrate its subtle regulation and its strategic function in specific signaling and as part of adaptor protein complexes. These data suggest that DGKζ offers new opportunities for therapeutic manipulation of lipid metabolism.     

The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses

Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor‐infiltrating CD4 and CD8 T cells. The Peli1‐deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild‐type T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1‐inhibitory proteins, TSC1 and TSC2. Peli1 mediates non‐degradative ubiquitination of TSC1, thereby promoting TSC1‐TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1‐mediated actions on T cell metabolism and antitumor immunity.     

Effect of metabolism on the immune microenvironment of breast cancer

Breast cancer (BC) is a highly prevalent primary malignancy worldwide with poor prognosis. Despite the development of aggressive interventions, mortality due to BC remains high. BC cells reprogram nutrient metabolism to adapt to the energy acquisition and progression of the tumor.The metabolic changes in cancer cells are closely related to the abnormal function and effect of immune cells and immune factors, including chemokines, cytokines, and other related effector molecules in the tumor microenvironment (TME), leading to tumor immune escape, whereby the complex crosstalk between immune cells and cancer cells has been considered the key mechanism regulating cancer progression. In this review, we summarized the latest findings on metabolism-related processes in the immune microenvironment during BC progression. Our findings showing the impact of metabolism on the immune microenvironment may suggest new strategies for regulating the immune microenvironment and attenuating BC through metabolic interventions.     

Metabolic Reprogramming towards Aerobic Glycolysis Correlates with Greater Proliferative Ability and Resistance to Metabolic Inhibition in CD8 versus CD4 T Cells

T lymphocytes (T cells) undergo metabolic reprogramming after activation to provide energy and biosynthetic materials for growth, proliferation and differentiation. Distinct T cell subsets, however, adopt metabolic programs specific to support their needs. As CD4 T cells coordinate adaptive immune responses while CD8 T cells become cytotoxic effectors, we compared activation-induced proliferation and metabolic reprogramming of these subsets. Resting CD4 and CD8 T cells were metabolically similar and used a predominantly oxidative metabolism. Following activation CD8 T cells proliferated more rapidly. Stimulation led both CD4 and CD8 T cells to sharply increase glucose metabolism and adopt aerobic glycolysis as a primary metabolic program. Activated CD4 T cells, however, remained more oxidative and had greater maximal respiratory capacity than activated CD8 T cells. CD4 T cells were also associated with greater levels of ROS and increased mitochondrial content, irrespective of the activation context. CD8 cells were better able, however, to oxidize glutamine as an alternative fuel source. The more glycolytic metabolism of activated CD8 T cells correlated with increased capacity for growth and proliferation, along with reduced sensitivity of cell growth to metabolic inhibition. These specific metabolic programs may promote greater growth and proliferation of CD8 T cells and enhance survival in diverse nutrient conditions.