bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–01–08
fiveteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Early immune pressure makes tumors metabolically stronger.
  2. Assessing the Immune Regulatory Role of Metabolites In Vitro.
  3. Immunoediting instructs tumor metabolic reprogramming to support immune evasion.
  4. Thioredoxin-interacting protein is essential for memory T cell formation via the regulation of the redox metabolism.
  5. The extrinsic factors important to the homeostasis of allergen-specific memory CD4 T cells.
  6. Meta-hallmarks of aging and cancer.
  7. T cells drive aging of the brain.
  8. Immune system modulation in aging: Molecular mechanisms and therapeutic targets.
  9. Lactate metabolism is essential in early-onset mitochondrial myopathy.
  10. Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib.
  11. Hallmarks of aging: An expanding universe.
  12. Glial Cell Metabolic Profile Upon Iron Deficiency: Oligodendroglial and Astroglial Casualties of Bioenergetic Adjustments.
  13. Cellular Senescence and Ageing.
  14. Illuminating lactate in cells, mice, and patient samples.
  15. STAT proteins in cancer: orchestration of metabolism.
  1. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00546-0. [Epub ahead of print]35(1): 3-5
    Early immune pressure makes tumors metabolically stronger.
    Sujing Yuan, Hongbo Chi.
      Metabolic communication in the tumor microenvironment underscores tumor-immune interactions and affects anti-tumor immunity, yet cell-extrinsic signals driving tumor metabolic remodeling are incompletely understood. In this issue, Tsai et al. show that during initial tumorigenesis, T cell-derived IFNγ triggers STAT3 activation and c-Myc-dependent alterations of tumor cell metabolism, which potentiates immune evasion.
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.009
  2. Methods Mol Biol. 2023 ;2614 109-120
    Assessing the Immune Regulatory Role of Metabolites In Vitro.
    Sarah McPhedran, Junu Choe, Sarah MacPherson, Gabrielle Kowalchuk, Vanessa Chan, Marisa K Kilgour, Julian J Lum.
      One method of immune evasion that cancer cells employ is the secretion of immune regulatory metabolites into the tumor microenvironment (TME). These metabolites can promote immunosuppressive cell subsets, while inhibiting key tumor-killing subsets, such as T cells. Thus, the identification of these metabolites may help develop methods for improving cell-based therapy. However, after identifying a potential immune regulatory metabolite, it is crucial to assess the impacts of the metabolite on T cell immunobiology. In this chapter, we describe an in vitro method of testing and analyzing the influence of a specific metabolite on T cell proliferation and function.
    Keywords:  Human T cells; Immunosuppressive; Metabolites; T cell function
    DOI:  https://doi.org/10.1007/978-1-0716-2914-7_8
  3. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00540-X. [Epub ahead of print]35(1): 118-133.e7
    Immunoediting instructs tumor metabolic reprogramming to support immune evasion.
    Chin-Hsien Tsai, Yu-Ming Chuang, Xiaoyun Li, Yi-Ru Yu, Sheue-Fen Tzeng, Shao Thing Teoh, Katherine E Lindblad, Mario Di Matteo, Wan-Chen Cheng, Pei-Chun Hsueh, Kung-Chi Kao, Hana Imrichova, Likun Duan, Hector Gallart-Ayala, Pei-Wen Hsiao, Massimiliano Mazzone, Julijana Ivanesevic, Xiaojing Liu, Karin E de Visser, Amaia Lujambio, Sophia Y Lunt, Susan M Kaech, Ping-Chih Ho.
      Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.
    Keywords:  IFNγ; Myc; STAT3; immunoediting; immunosurveillance; tumor immunology
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.003
  4. Proc Natl Acad Sci U S A. 2023 Jan 10. 120(2): e2218345120
    Thioredoxin-interacting protein is essential for memory T cell formation via the regulation of the redox metabolism.
    Kota Kokubo, Kiyoshi Hirahara, Masahiro Kiuchi, Kaori Tsuji, Yuki Shimada, Yuri Sonobe, Rie Shinmi, Takahisa Hishiya, Chiaki Iwamura, Atsushi Onodera, Toshinori Nakayama.
      CD4+ memory T cells are central to long-lasting protective immunity and are involved in shaping the pathophysiology of chronic inflammation. While metabolic reprogramming is critical for the generation of memory T cells, the mechanisms controlling the redox metabolism in memory T cell formation remain unclear. We found that reactive oxygen species (ROS) metabolism changed dramatically in T helper-2 (Th2) cells during the contraction phase in the process of memory T cell formation. Thioredoxin-interacting protein (Txnip), a regulator of oxidoreductase, regulated apoptosis by scavenging ROS via the nuclear factor erythroid 2-related factor 2 (Nrf2)-biliverdin reductase B (Blvrb) pathway. Txnip regulated the pathology of chronic airway inflammation in the lung by controlling the generation of allergen-specific pathogenic memory Th2 cells in vivo. Thus, the Txnip-Nrf2-Blvrb axis directs ROS metabolic reprogramming in Th2 cells and is a potential therapeutic target for intractable chronic inflammatory diseases.
    Keywords:  biliverdin reductase B (Blvrb); memory Th2 cells; nuclear factor-erythroid factor 2-related factor 2 (Nrf2); reactive oxygen species (ROS); thioredoxin-interacting protein (Txnip)
    DOI:  https://doi.org/10.1073/pnas.2218345120
  5. Front Immunol. 2022 ;13 1080855
    The extrinsic factors important to the homeostasis of allergen-specific memory CD4 T cells.
    Aryeong Choi, Yong Woo Jung, Hanbyeul Choi.
      Memory T cells, which are generated after the primary immune response to cognate antigens, possess unique features compared to naïve or effector T cells. These memory T cells are maintained for a long period of time and robustly reactivate in lymphoid or peripheral tissues where they re-encounter antigens. Environments surrounding memory T cells are importantly involved in the process of the maintenance and reactivation of these T cells. Although memory T cells are generally believed to be formed in response to acute infections, the pathogenesis and persistence of chronic inflammatory diseases, including allergic diseases, are also related to the effector functions of memory CD4 T cells. Thus, the factors involved in the homeostasis of allergen-specific memory CD4 T cells need to be understood to surmount these diseases. Here, we review the characteristics of allergen-specific memory CD4 T cells in allergic diseases and the importance of extrinsic factors for the homeostasis and reactivation of these T cells in the view of mediating persistence, recurrence, and aggravation of allergic diseases. Overall, this review provides a better understanding of memory CD4 T cells to devise effective therapeutic strategies for refractory chronic inflammatory diseases.
    Keywords:  allergen-specific memory CD4 T cells; chronic inflammatory diseases; extrinsic factors; homeostasis; microenvironments
    DOI:  https://doi.org/10.3389/fimmu.2022.1080855
  6. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00492-2. [Epub ahead of print]35(1): 12-35
    Meta-hallmarks of aging and cancer.
    Carlos López-Otín, Federico Pietrocola, David Roiz-Valle, Lorenzo Galluzzi, Guido Kroemer.
      Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
    Keywords:  aging; cancer; carcinogenesis; metabolism; oncogenesis; tumor progression
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.001
  7. Nat Immunol. 2023 Jan;24(1): 12-13
    T cells drive aging of the brain.
    Adrian Liston, Lidia Yshii.
      
    DOI:  https://doi.org/10.1038/s41590-022-01390-0
  8. Front Immunol. 2022 ;13 1059173
    Immune system modulation in aging: Molecular mechanisms and therapeutic targets.
    Bulmaro Cisneros, Ian García-Aguirre, Juan Unzueta, Isabel Arrieta-Cruz, Oscar González-Morales, Juan M Domínguez-Larrieta, Aura Tamez-González, Gerardo Leyva-Gómez, Jonathan J Magaña.
      The function of the immune system declines during aging, compromising its response against pathogens, a phenomenon termed as "immunosenescence." Alterations of the immune system undergone by aged individuals include thymic involution, defective memory T cells, impaired activation of naïve T cells, and weak memory response. Age-linked alterations of the innate immunity comprise perturbed chemotactic, phagocytic, and natural killing functions, as well as impaired antigen presentation. Overall, these alterations result in chronic low-grade inflammation (inflammaging) that negatively impacts health of elderly people. In this review, we address the most relevant molecules and mechanisms that regulate the relationship between immunosenescence and inflammaging and provide an updated description of the therapeutic strategies aimed to improve immunity in aged individuals.
    Keywords:  aging; chronic infections; immune system; immunosenescence; inflammaging
    DOI:  https://doi.org/10.3389/fimmu.2022.1059173
  9. Sci Adv. 2023 Jan 04. 9(1): eadd3216
    Lactate metabolism is essential in early-onset mitochondrial myopathy.
    Zhenkang Chen, Bogdan Bordieanu, Rushendhiran Kesavan, Nicholas P Lesner, Siva Sai Krishna Venigalla, Spencer D Shelton, Ralph J DeBerardinis, Prashant Mishra.
      Myopathies secondary to mitochondrial electron transport chain (ETC) dysfunction can result in devastating disease. While the consequences of ETC defects have been extensively studied in culture, little in vivo data are available. Using a mouse model of severe, early-onset mitochondrial myopathy, we characterized the proteomic, transcriptomic, and metabolic characteristics of disease progression. Unexpectedly, ETC dysfunction in muscle results in reduced expression of glycolytic enzymes in our animal model and patient muscle biopsies. The decrease in glycolysis was mediated by loss of constitutive Hif1α signaling, down-regulation of the purine nucleotide cycle enzyme AMPD1, and activation of AMPK. In vivo isotope tracing experiments indicated that myopathic muscle relies on lactate import to supply central carbon metabolites. Inhibition of lactate import reduced steady-state levels of tricarboxylic acid cycle intermediates and compromised the life span of myopathic mice. These data indicate an unexpected mode of metabolic reprogramming in severe mitochondrial myopathy that regulates disease progression.
    DOI:  https://doi.org/10.1126/sciadv.add3216
  10. Cancer Immunol Immunother. 2023 Jan 05.
    Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib.
    Lukas Häselbarth, Axel Karow, Kristin Mentz, Martin Böttcher, Oisin Roche-Lancaster, Manuela Krumbholz, Regina Jitschin, Dimitrios Mougiakakos, Markus Metzler.
      T cell function is central to immune reconstitution and control of residual chronic myeloid leukemia (CML) cells after treatment initiation and is associated with achieving deep molecular response as a prerequisite for treatment-free remission, the ultimate therapeutic goal in CML. ATP-pocket-binding tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib are widely used for treating CML, but they have shown to inhibit T cell function as an "off-target" effect. Therefore, we tested asciminib, the first-in-class BCR::ABL1 fusion protein inhibitor specifically targeting the ABL myristoyl pocket (STAMP) and compared its effects on T cell function with imatinib, dasatinib, and nilotinib. Whereas all four TKIs inhibited the expression of the co-stimulatory protein CD28, the amino acid transporter CD98, proliferation, and secretion of pro-inflammatory cytokines IFNγ, IL-6, and IL-17A upon T cell stimulation, asciminib had less impact on PD-1, activation markers, and IL-2 secretion. T cells treated with asciminib and the other TKIs maintained their ability to mobilize their respiratory capacity and glycolytic reserve, which is an important surrogate for metabolic fitness and flexibility. Overall, we found milder inhibitory effects of asciminib on T cell activation, which might be beneficial for the immunological control of residual CML cells.
    Keywords:  Activity; Asciminib; CML; Metabolism; T cell; TKI
    DOI:  https://doi.org/10.1007/s00262-022-03361-8
  11. Cell. 2022 Dec 26. pii: S0092-8674(22)01377-0. [Epub ahead of print]
    Hallmarks of aging: An expanding universe.
    Carlos López-Otín, Maria A Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer.
      Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
    DOI:  https://doi.org/10.1016/j.cell.2022.11.001
  12. Mol Neurobiol. 2023 Jan 03.
    Glial Cell Metabolic Profile Upon Iron Deficiency: Oligodendroglial and Astroglial Casualties of Bioenergetic Adjustments.
    María Victoria Rosato-Siri, Pamela V Martino Adami, María Eugenia Guitart, Sandra Verstraeten, Laura Morelli, Jorge Correale, Juana María Pasquini.
      Iron deficiency (ID) represents one of the most prevalent nutritional deficits, affecting almost two billion people worldwide. Gestational iron deprivation induces hypomyelination due to oligodendroglial maturation deficiencies and is thus a useful experimental model to analyze oligodendrocyte (OLG) requirements to progress to a mature myelinating state. A previous proteomic study in the adult ID brain by our group demonstrated a pattern of dysregulated proteins involved in the tricarboxylic acid cycle and mitochondrial dysfunction. The aim of the present report was to assess bioenergetics metabolism in primary cultures of OLGs and astrocytes (ASTs) from control and ID newborns, on the hypothesis that the regulation of cell metabolism correlates with cell maturation. Oxygen consumption and extracellular acidification rates were measured using a Seahorse extracellular flux analyzer. ID OLGs and ASTs both exhibited decreased spare respiratory capacity, which indicates that ID effectively induces mitochondrial dysfunction. A decrease in glycogen granules was observed in ID ASTs, and an increase in ROS production was detected in ID OLGs. Immunolabeling of structural proteins showed that mitochondrial number and size were increased in ID OLGs, while an increased number of smaller mitochondria was observed in ID ASTs. These results reflect an unfavorable bioenergetic scenario in which ID OLGs fail to progress to a myelinating state, and indicate that the regulation of cell metabolism may impact cell fate decisions and maturation.
    Keywords:  Astrocytes; Bioenergetic parameters; Glial cell metabolism; Glycogen consumption; Iron deficiency; Mitochondrial dysfunction; Oligodendrocytes
    DOI:  https://doi.org/10.1007/s12035-022-03149-y
  13. Subcell Biochem. 2023 ;102 139-173
    Cellular Senescence and Ageing.
    Rebecca Reed, Satomi Miwa.
      Cellular senescence has become a subject of great interest within the ageing research field over the last 60 years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone. This chapter will also examine how senescent cell accumulation presents in these different tissues, along with their roles in disease development. Finally, there is much focus on developing treatments for senescent cell accumulation in advanced age as a method of alleviating age-related disease. We will discuss here the various senolytic and senostatic treatment approaches and their successes and limitations, and the innovative new strategies being developed to address the differing effects of cellular senescence in ageing and disease.
    Keywords:  Age-related disease; Ageing; SA-β-Gal; SASP; Senescence; Senolytic; Senostatic; Telomeres
    DOI:  https://doi.org/10.1007/978-3-031-21410-3_7
  14. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00544-7. [Epub ahead of print]35(1): 5-7
    Illuminating lactate in cells, mice, and patient samples.
    Zefan Li, Hui-Wang Ai.
      Lactate has emerged as a central metabolic fuel and an important signaling molecule. In this issue of Cell Metabolism, Li et al. develop a high-quality lactate sensor, allowing them to monitor lactate levels in cells, subcellular organelles, live mice, and human body fluids.
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.007
  15. Nat Rev Cancer. 2023 Jan 03.
    STAT proteins in cancer: orchestration of metabolism.
    Yi-Jia Li, Chunyan Zhang, Antons Martincuks, Andreas Herrmann, Hua Yu.
      Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00537-3
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