bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–10–06
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.
  2. Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy.
  3. γδ T-Cell Immunophenotype for the Study of Human Aging.
  4. Beyond exhaustion: the unique characteristics of CD8+ T cell dysfunction in chronic HBV infection.
  5. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
  6. Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T-cell stemness and improves adoptive T-cell therapy.
  7. Tim-3 Is Required for Regulatory T Cell-Mediated Promotion of T Cell Exhaustion and Viral Persistence during Chronic Lymphocytic Choriomeningitis Virus Infection.
  8. Age-associated changes in innate and adaptive immunity: role of the gut microbiota.
  9. ICOS limits memory-like properties and function of exhausted PD-1 + CD8 T cells.
  10. Midkine as a driver of age-related changes and increase in mammary tumorigenesis.
  11. Method to Assess Immunosenescent CD8+ T Cells in Respiratory Viral Infections.
  12. Investigation of Signaling in Primary Populations of Human Senescent T Cells.
  1. Biochem Biophys Res Commun. 2024 Sep 24. pii: S0006-291X(24)01274-9. [Epub ahead of print]734 150738
    Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.
    Min Liu, Xinyue Fu, Qinghe Yi, Enhong Xu, Longbao Dong.
      CD8+ T cells play a crucial role in anti-tumor immunity, but their function can be impaired by exhaustion induced by prolonged antigen stimulation. Mitochondrial dysfunction, a hallmark of the tumor microenvironment (TME), has been linked to various pathologies, but its specific role in CD8+ T cell exhaustion remains underexplored. Here, we established an in vitro model of CD8+ T cell exhaustion by co-culturing OVA-specific OT1 CD8+ T cells with OVA-expressing MC38 tumor cells. Next, we investigated the impact of mitochondrial dysfunction on exhaustion using pharmacological inhibitors targeting the electron transport chain. The role of the mitochondrial complex I component NDUFA10 was further examined through genetic knockout in CD8+ T cells using CRISPR-Cas9. Inhibition of the mitochondrial electron transport chain significantly accelerated CD8+ T cell exhaustion in vitro. Knockout of NDUFA10 in CD8+ T cells led to enhanced tumor growth and increased exhaustion of tumor-infiltrating CD8+ T cells in a Rag1-/- tumor-bearing transfer model. This study highlights the critical role of mitochondrial function in regulating CD8+ T cell exhaustion and anti-tumor activity, providing new insights into the metabolic underpinnings of immune dysfunction in cancer.
    Keywords:  CD8(+) T cell; Exhaustion; Mitochondrion
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150738
  2. J Exp Clin Cancer Res. 2024 Sep 28. 43(1): 266
    Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy.
    Zhouchi Yao, Yayun Zeng, Cheng Liu, Huimin Jin, Hong Wang, Yue Zhang, Chengming Ding, Guodong Chen, Daichao Wu.
      Vigorous CD8+ T cells play a crucial role in recognizing tumor cells and combating solid tumors. How T cells efficiently recognize and target tumor antigens, and how they maintain the activity in the "rejection" of solid tumor microenvironment, are major concerns. Recent advances in understanding of the immunological trajectory and lifespan of CD8+ T cells have provided guidance for the design of more optimal anti-tumor immunotherapy regimens. Here, we review the newly discovered methods to enhance the function of CD8+ T cells against solid tumors, focusing on optimizing T cell receptor (TCR) expression, improving antigen recognition by engineered T cells, enhancing signal transduction of the TCR-CD3 complex, inducing the homing of polyclonal functional T cells to tumors, reversing T cell exhaustion under chronic antigen stimulation, and reprogramming the energy and metabolic pathways of T cells. We also discuss how to participate in the epigenetic changes of CD8+ T cells to regulate two key indicators of anti-tumor responses, namely effectiveness and persistence.
    Keywords:  CD8+ T cell; Engineered T cell receptor -T cells; Gene editing; Immune checkpoint; Immune reprogramming; Immunotherapy; Metabolic reprogramming; Solid tumor; T cell redirection
    DOI:  https://doi.org/10.1186/s13046-024-03195-5
  3. Methods Mol Biol. 2025 ;2857 45-59
    γδ T-Cell Immunophenotype for the Study of Human Aging.
    Anna Maria Corsale, Marta Di Simone, Serena Meraviglia, Calogero Caruso.
      Flow cytometry serves as a crucial tool in immunology, allowing for the detailed analysis of immune cell populations. γδ T cells, a subset of T cells, play pivotal roles in immune surveillance and immune aging. Assessing the phenotype and functional capabilities of γδ T cells isolated from whole blood or tissue within the context of human aging yields invaluable insights into the dynamic changes affecting immune function, tissue homeostasis, susceptibility to infections, and inflammatory responses.
    Keywords:  Cell expansion; Density gradient centrifugation; Flow cytometry; Functional assays; Immunomagnetic separation; Tumor-infiltrating lymphocytes; γδ T cells
    DOI:  https://doi.org/10.1007/978-1-0716-4128-6_5
  4. Nat Rev Immunol. 2024 Oct 04.
    Beyond exhaustion: the unique characteristics of CD8+ T cell dysfunction in chronic HBV infection.
    Robert Thimme, Antonio Bertoletti, Matteo Iannacone.
      
    DOI:  https://doi.org/10.1038/s41577-024-01097-3
  5. Cell Death Discov. 2024 Sep 30. 10(1): 417
    Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
    Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, Javier A Menendez.
      Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-02184-z
  6. Cancer Immunol Res. 2024 Oct 04.
    Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T-cell stemness and improves adoptive T-cell therapy.
    Yingqin Hou, Jaroslav Zak, Yujie Shi, Isaraphorn Pratumchai, Brandon Dinner, Wenjian Wang, Ke Qin, Evan W Weber, John R Teijaro, Peng Wu.
      The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we have demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation. Tazemetostat induced T-cell epigenetic reprogramming and increased the expression of the self-renewal T-cell transcription factor TCF1 by reducing H3K27 methylation at its promoter preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with tazemetostat exhibited superior antitumor immunity, especially when used in combination with anti-PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0089
  7. J Immunol. 2024 Sep 30. pii: ji2400119. [Epub ahead of print]
    Tim-3 Is Required for Regulatory T Cell-Mediated Promotion of T Cell Exhaustion and Viral Persistence during Chronic Lymphocytic Choriomeningitis Virus Infection.
    Hector M Nieves-Rosado, Hridesh Banerjee, Angela Gocher-Demske, Priyanka Manandhar, Isha Mehta, Ogechukwu Ezenwa, Bingxian Xie, Ben Murter, Jishnu Das, Dario A A Vignali, Greg M Delgoffe, Lawrence P Kane.
      Expression of T cell Ig and mucin domain-containing protein 3 (Tim-3) is upregulated on regulatory T cells (Tregs) during chronic viral infections. In several murine and human chronic infections, the expression of Tim-3 is associated with poor control of viral burden and impaired antiviral immune responses. However, the role of Tim-3+ Tregs during persistent viral infections has not been fully defined. We employed an inducible Treg-specific Tim-3 loss-of-function (Tim-3 Treg knockout) murine model to dissect the role of Tim-3 on Tregs during chronic lymphocytic choriomeningitis virus infection. Tim-3 Treg knockout mice exhibited a decrease in morbidity, a more potent virus-specific T cell response, and a significant decrease in viral burden. These mice also had a reduction in the frequency of PD-1+Tim-3+ and PD-1+Tox+ gp33-specific exhausted CD8+ T cells. Our findings demonstrate that modulation of a single surface protein on Tregs can lead to a reduction in viral burden, limit T cell exhaustion, and enhance gp33-specific T cell response. These studies may help to identify Tim-3-directed therapies for the management of persistent infections and cancer.
    DOI:  https://doi.org/10.4049/jimmunol.2400119
  8. Front Immunol. 2024 ;15 1421062
    Age-associated changes in innate and adaptive immunity: role of the gut microbiota.
    Haoyu Gao, Eugenie Nepovimova, Vojtech Adam, Zbynek Heger, Marian Valko, Qinghua Wu, Kamil Kuca.
      Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.
    Keywords:  adaptive immunity; aging; cGAS-STING; gut microbiota; gut microbiota aging; innate immunity
    DOI:  https://doi.org/10.3389/fimmu.2024.1421062
  9. bioRxiv. 2024 Sep 20. pii: 2024.09.16.611518. [Epub ahead of print]
    ICOS limits memory-like properties and function of exhausted PD-1 + CD8 T cells.
    Etienne Humblin, Isabel Korpas, Nataliya Prokhnevska, Abishek Vaidya, Jiahua Lu, Verena van der Heide, Dan Filipescu, Tesia Bobrowski, Adam Marks, Matthew D Park, Emily Bernstein, Brian D Brown, Amaia Lujambio, David Dominguez-Sola, Brad R Rosenberg, Alice O Kamphorst.
      During persistent antigen stimulation, PD-1 + CD8 T cells are maintained by progenitor exhausted PD-1 + TCF-1 + CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1 + CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory-like features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1 + CD8 T cells and delayed tumor growth. Overall, we show that ICOS limits CD8 T cell responses during chronic antigen exposure.
    DOI:  https://doi.org/10.1101/2024.09.16.611518
  10. Cancer Cell. 2024 Sep 26. pii: S1535-6108(24)00350-7. [Epub ahead of print]
    Midkine as a driver of age-related changes and increase in mammary tumorigenesis.
    Pengze Yan, Ernesto Rojas Jimenez, Zheqi Li, Triet Bui, Marco Seehawer, Jun Nishida, Pierre Foidart, Laura E Stevens, Yingtian Xie, Miguel Munoz Gomez, So Yeon Park, Henry W Long, Kornelia Polyak.
      Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.
    Keywords:  aging; breast cancer risk; breast tumorigenesis; mammary tumors; midkine; single-cell profiling
    DOI:  https://doi.org/10.1016/j.ccell.2024.09.002
  11. Methods Mol Biol. 2025 ;2857 33-43
    Method to Assess Immunosenescent CD8+ T Cells in Respiratory Viral Infections.
    Olivia B Parks, John V Williams.
      Immunosenescence is a well-characterized phenomenon that occurs with increasing age in all immune and somatic cells. In order to best study immunosenescence, it is imperative to develop methods to accurately identify immunosenescent cells. Elderly patients are known to have impaired immune responses to respiratory viruses, and it is hypothesized that this is due, in part, to immunosenescent, terminally exhausted CD8+ T cells. To test this hypothesis, we developed an aged mouse model and a flow cytometry protocol using the Cytek® Aurora to assess the CD8+ T-cell response during respiratory viral infection and identify immunosenescent CD8+ T cells. This protocol and our aged mouse model have great potential to be incredibly valuable for future studies elucidating how to rejuvenate and possibly reverse immunosenescent CD8+ T cells, which could improve the immune response to respiratory viruses in this at-risk population.
    Keywords:  Aged; CD8+ T cells; Respiratory viral infection
    DOI:  https://doi.org/10.1007/978-1-0716-4128-6_4
  12. Methods Mol Biol. 2025 ;2857 61-77
    Investigation of Signaling in Primary Populations of Human Senescent T Cells.
    Alessio Lanna, Federica Rinaldi.
      Mitogen-activated protein kinases, a family of three stress-related kinases, the Erks and Jnks and p38s, are activated by three-layer transphosphorylation cascades and are important for the activation, differentiation, and effector functions of lymphocytes. Recent studies on the aged immune systems from both humans and mice have uncovered a different mode of MAPK signaling that is independent of canonical activation cascades and instead occurs through simultaneous self-phosphorylation reactions within the sestrin-MAPK activation complex (sMAC), an immune-inhibitory complex not previously observed. In this chapter, we discuss methodologies to study these pathways at the population and single cell level, which allows rejuvenating immune cell differentiation and fate.
    Keywords:  Cell signaling; MAPK; Mitogen-activated protein kinases; Senescence; T lymphocytes; sMAC
    DOI:  https://doi.org/10.1007/978-1-0716-4128-6_6
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:17.