bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–03–17
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Unlocking the potential of T-cell metabolism reprogramming: Advancing single-cell approaches for precision immunotherapy in tumour immunity.
  2. Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.
  3. Understanding the pathogenic significance of altered calcium-calmodulin signaling in T cells in autoimmune diseases.
  4. Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
  5. Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
  6. Regulation of innate-like activities of neonatal CD8+ T cells.
  7. The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.
  8. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.
  9. Premature aging in genetic diseases: what conclusions can be drawn for physiological aging.
  10. Gene editing technology to improve antitumor T-cell functions in adoptive immunotherapy.
  11. Enhancing healthy aging with small molecules: A mitochondrial perspective.
  12. The aged microenvironment impairs BCL6 and CD40L induction in CD4+ T follicular helper cell differentiation.
  13. CD5 blockade, a novel immune checkpoint inhibitor, enhances T cell anti-tumour immunity and delays tumour growth in mice harbouring poorly immunogenic 4T1 breast tumour homografts.
  14. Aging from adipose accumulation of antibodies.
  1. Clin Transl Med. 2024 Mar;14(3): e1620
    Unlocking the potential of T-cell metabolism reprogramming: Advancing single-cell approaches for precision immunotherapy in tumour immunity.
    Lihaoyun Huang, Haitao Li, Cangang Zhang, Quan Chen, Zaoqu Liu, Jian Zhang, Peng Luo, Ting Wei.
      As single-cell RNA sequencing enables the detailed clustering of T-cell subpopulations and facilitates the analysis of T-cell metabolic states and metabolite dynamics, it has gained prominence as the preferred tool for understanding heterogeneous cellular metabolism. Furthermore, the synergistic or inhibitory effects of various metabolic pathways within T cells in the tumour microenvironment are coordinated, and increased activity of specific metabolic pathways generally corresponds to increased functional activity, leading to diverse T-cell behaviours related to the effects of tumour immune cells, which shows the potential of tumour-specific T cells to induce persistent immune responses. A holistic understanding of how metabolic heterogeneity governs the immune function of specific T-cell subsets is key to obtaining field-level insights into immunometabolism. Therefore, exploring the mechanisms underlying the interplay between T-cell metabolism and immune functions will pave the way for precise immunotherapy approaches in the future, which will empower us to explore new methods for combating tumours with enhanced efficacy.
    Keywords:  T-cell metabolism; immunotherapy; metabolic reprogramming; single-cell RNA sequencing; tumour immunity
    DOI:  https://doi.org/10.1002/ctm2.1620
  2. Cell Rep Med. 2024 Mar 01. pii: S2666-3791(24)00109-5. [Epub ahead of print] 101465
    Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.
    Michael St Paul, Samuel D Saibil, Meghan Kates, SeongJun Han, Scott C Lien, Rob C Laister, Kebria Hezaveh, Andreas Kloetgen, Susanne Penny, Tingxi Guo, Carlos Garcia-Batres, Logan K Smith, Douglas C Chung, Alisha R Elford, Azin Sayad, Devanand Pinto, Tak W Mak, Naoto Hirano, Tracy McGaha, Pamela S Ohashi.
      The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.
    Keywords:  4-1BB; CD8(+) T cell; GCN2; Halofuginone; adoptive Cell therapy; autophagy; immunometabolism; immunotherapy
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101465
  3. Clin Immunol. 2024 Mar 07. pii: S1521-6616(24)00068-8. [Epub ahead of print] 110177
    Understanding the pathogenic significance of altered calcium-calmodulin signaling in T cells in autoimmune diseases.
    Tomohiro Koga.
      Calcium/calmodulin-dependent protein kinase IV (CaMK4) serves as a pivotal mediator in the regulation of gene expression, influencing the activity of transcription factors within a variety of immune cells, including T cells. Altered CaMK4 signaling is implicated in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, which are characterized by dysregulated immune responses and clinical complexity. These conditions share common disturbances in immune cell functionality, cytokine production, and autoantibody generation, all of which are associated with disrupted calcium-calmodulin signaling. This review underscores the consequences of dysregulated CaMK4 signaling across these diseases, with an emphasis on its impact on Th17 differentiation and T cell metabolism-processes central to maintaining immune homeostasis. A comprehensive understanding of roles of CaMK4 in gene regulation across various autoimmune disorders holds promise for the development of targeted therapies, particularly for diseases driven by Th17 cell dysregulation.
    Keywords:  Calcium/calmodulin-dependent protein kinase IV (CaMK4); Interleukin (IL)-17; Rheumatoid arthritis (RA); Systemic lupus erythematosus (SLE); T cells
    DOI:  https://doi.org/10.1016/j.clim.2024.110177
  4. R Soc Open Sci. 2024 Mar;11(3): 231574
    Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
    Mudita Shukla, Rupa Bhowmick, Piyali Ganguli, Ram Rup Sarkar.
      Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour-immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.
    Keywords:  metabolic reprogramming; signalling-metabolic cross-talks; system modelling; tumour–immune interaction
    DOI:  https://doi.org/10.1098/rsos.231574
  5. Nat Commun. 2024 Mar 11. 15(1): 2203
    Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
    Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.
      The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
    DOI:  https://doi.org/10.1038/s41467-024-46377-7
  6. Nat Rev Immunol. 2024 Mar 11.
    Regulation of innate-like activities of neonatal CD8+ T cells.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01020-w
  7. J Leukoc Biol. 2024 Mar 11. pii: qiae060. [Epub ahead of print]
    The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.
    Fernando Díaz-Basilio, Moisés Vergara-Mendoza, Jessica Romero-Rodríguez, Sharik Hernández-Rizo, Alejandro Escobedo-Calvario, Luis-León Fuentes-Romero, Santiago Pérez-Patrigeon, Akio Murakami-Ogasawara, María Gomez-Palacio, Gustavo Reyes-Terán, Wei Jiang, Joel-Armando Vázquez-Pérez, Álvaro Marín-Hernández, Dámaris-Priscila Romero-Rodríguez, María-Concepción Gutiérrez-Ruiz, Mónica Viveros-Rogel, Enrique Espinosa.
      Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.
    Keywords:  Acquired Immunodeficiency Syndrome; CD38 Antigen; Immunity; Memory T Cells; Metabolism; Receptor-CD3 Complex
    DOI:  https://doi.org/10.1093/jleuko/qiae060
  8. Immunity. 2024 Mar 06. pii: S1074-7613(24)00090-6. [Epub ahead of print]
    Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.
    Jingjing Cong, Pianpian Liu, Zili Han, Wei Ying, Chaoliang Li, Yifei Yang, Shuling Wang, Jianbo Yang, Fei Cao, Juntao Shen, Yu Zeng, Yu Bai, Congzhao Zhou, Lilin Ye, Rongbin Zhou, Chunjun Guo, Chunlei Cang, Dennis L Kasper, Xinyang Song, Lei Dai, Linfeng Sun, Wen Pan, Shu Zhu.
      Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.
    Keywords:  CD8(+) T cell; anti-tumor immunity; deoxycholic acid; effector function; microbiota
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.014
  9. Front Aging. 2023 ;4 1327833
    Premature aging in genetic diseases: what conclusions can be drawn for physiological aging.
    Filip Milosic, Markus Hengstschläger, Selma Osmanagic-Myers.
      According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability, telomere attrition, loss of proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic hallmarks that represent response to damage (deregulated nutrient sensing, cellular senescence, mitochondrial dysfunction) and integrative hallmarks that represent culprits of the phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast to physiological aging, premature aging diseases are driven by one or two distinct primary causes of aging, such as genomic instability in the case of Werner syndrome (WS), each displaying other hallmarks of aging to a variable extent. In this review we will focus on primary causes of well-investigated premature aging diseases Hutchinson-Gilford progeria syndrome (HGPS), WS, and Cockayne syndrome (CS) and for each provide an overview of reported aging hallmarks to elucidate resemblance to physiological aging on the mechanistic level and in the context of characteristic age-related diseases. Ubiquitous and tissue specific animal models of premature aging diseases will be discussed as useful tools to decipher fundamental aging-related mechanisms and develop intervention strategies to combat premature aging and age-related diseases.
    Keywords:  HGPS; aging; cockayne syndrome; premature aging; progeroid; senescence; werner syndrome
    DOI:  https://doi.org/10.3389/fragi.2023.1327833
  10. Inflamm Regen. 2024 Mar 11. 44(1): 13
    Gene editing technology to improve antitumor T-cell functions in adoptive immunotherapy.
    Yusuke Ito, Satoshi Inoue, Yuki Kagoya.
      Adoptive immunotherapy, in which tumor-reactive T cells are prepared in vitro for adoptive transfer to the patient, can induce an objective clinical response in specific types of cancer. In particular, chimeric antigen receptor (CAR)-redirected T-cell therapy has shown robust responses in hematologic malignancies. However, its efficacy against most of the other tumors is still insufficient, which remains an unmet medical need. Accumulating evidence suggests that modifying specific genes can enhance antitumor T-cell properties. Epigenetic factors have been particularly implicated in the remodeling of T-cell functions, including changes to dysfunctional states such as terminal differentiation and exhaustion. Genetic ablation of key epigenetic molecules prevents the dysfunctional reprogramming of T cells and preserves their functional properties.Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-based gene editing is a valuable tool to enable efficient and specific gene editing in cultured T cells. A number of studies have already identified promising targets to improve the therapeutic efficacy of CAR-T cells using genome-wide or focused CRISPR screening. In this review, we will present recent representative findings on molecular insights into T-cell dysfunction and how genetic modification contributes to overcoming it. We will also discuss several technical advances to achieve efficient gene modification using the CRISPR and other novel platforms.
    Keywords:  Adoptive immunotherapy; CRISPR/Cas9; Chimeric antigen receptor; DNA methylation; Epigenetics; Memory T cell; PRDM1; T-cell exhaustion
    DOI:  https://doi.org/10.1186/s41232-024-00324-7
  11. Med Res Rev. 2024 Mar 14.
    Enhancing healthy aging with small molecules: A mitochondrial perspective.
    Xiujiao Qin, Hongyuan Li, Huiying Zhao, Le Fang, Xiaohui Wang.
      The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.
    Keywords:  aging; mitochondrial; mitophagy; redox homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1002/med.22034
  12. Aging Cell. 2024 Mar 13. e14140
    The aged microenvironment impairs BCL6 and CD40L induction in CD4+ T follicular helper cell differentiation.
    Jacob S Fisher, Irene Adán-Barrientos, Naveen R Kumar, Jessica N Lancaster.
      Weakened germinal center responses by the aged immune system result in diminished immunity against pathogens and reduced efficacy of vaccines. Prolonged contacts between activated B cells and CD4+ T cells are crucial to germinal center formation and T follicular helper cell (Tfh) differentiation, but it is unclear how aging impacts the quality of this interaction. Peptide immunization confirmed that aged mice have decreased expansion of antigen-specific germinal center B cells and reduced antibody titers. Furthermore, aging was associated with accumulated Tfh cells, even in naïve mice. Despite increased numbers, aged Tfh had reduced expression of master transcription factor BCL6 and increased expression of the ectonucleotidase CD39. In vitro activation revealed that proliferative capacity was maintained in aged CD4+ T cells, but not the costimulatory molecule CD40L. When activated in vitro by aged antigen-presenting cells, young CD4+ naïve T cells generated reduced numbers of activated cells with upregulated CD40L. To determine the contribution of cell-extrinsic influences on antigen-specific Tfh induction, young, antigen-specific B and CD4+ T cells were adoptively transferred into aged hosts prior to peptide immunization. Transferred cells had reduced expansion and differentiation into germinal center B cell and Tfh and reduced antigen-specific antibody titers when compared to young hosts. Young CD4+ T cells transferred aged hosts differentiated into Tfh cells with reduced PD-1 and BCL6 expression, and increased CD39 expression, though they maintained their mitochondrial capacity. These results highlight the role of the lymphoid microenvironment in modulating CD4+ T cell differentiation, which contributes to impaired establishment and maintenance of germinal centers.
    Keywords:  T follicular helper cells; aging; germinal center
    DOI:  https://doi.org/10.1111/acel.14140
  13. Front Immunol. 2024 ;15 1256766
    CD5 blockade, a novel immune checkpoint inhibitor, enhances T cell anti-tumour immunity and delays tumour growth in mice harbouring poorly immunogenic 4T1 breast tumour homografts.
    Faizah M Alotaibi, Wei-Ping Min, James Koropatnick.
      CD5 is a member of the scavenger receptor cysteine-rich superfamily that is expressed on T cells and a subset of B cells (B1a) cell and can regulate the T cell receptor signaling pathway. Blocking CD5 function may have therapeutic potential in treatment of cancer by enhancing cytotoxic T lymphocyte recognition and ablation of tumour cells. The effect of administering an anti-CD5 antibody to block or reduce CD5 function as an immune checkpoint blockade to enhance T cell anti-tumour activation and function in vivo has not been explored. Here we challenged mice with poorly immunogenic 4T1 breast tumour cells and tested whether treatment with anti-CD5 monoclonal antibodies (MAb) in vivo could enhance non-malignant T cell anti-tumour immunity and reduce tumour growth. Treatment with anti-CD5 MAb resulted in an increased fraction of CD8+ T cells compared to CD4+ T cell in draining lymph nodes and the tumour microenvironment. In addition, it increased activation and effector function of T cells isolated from spleens, draining lymph nodes, and 4T1 tumours. Furthermore, tumour growth was delayed in mice treated with anti-CD5 MAb. These data suggest that use of anti-CD5 MAb as an immune checkpoint blockade can both enhance activation of T cells in response to poorly immunogenic antigens and reduce tumour growth in vivo. Exploration of anti-CD5 therapies in treatment of cancer, alone and in combination with other immune therapeutic drugs, is warranted.
    Keywords:  CD5; T cell; cancer; drug; immune checkpoint inhibitors; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1256766
  14. Sci Signal. 2024 Mar 12. 17(827): eadp0688
    Aging from adipose accumulation of antibodies.
    Wei Wong.
      IgG accumulation in white adipose tissue contributes to aging-associated metabolic dysfunction.
    DOI:  https://doi.org/10.1126/scisignal.adp0688
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