bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–11–03
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
  2. Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
  3. The immunometabolic roots of aging.
  4. Targeting metabolic pathway enhance CAR-T potency for solid tumor.
  5. The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.
  6. Development of a Competitive Nutrient-Based T-Cell Immunotherapy Designed to Block the Adaptive Warburg Effect in Acute Myeloid Leukemia.
  7. How to feed mitochondria to T cells.
  8. N-acetyltransferase 10 is implicated in the pathogenesis of cycling T cell-mediated autoimmune and inflammatory disorders in mice.
  9. Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer.
  10. TrkB signalling regulates dopamine circuits and motor function through metabolic pathways.
  11. Dosage compensation in T cells.
  12. Age-dependent immune profile in healthy individuals: an original study, systematic review and meta-analysis.
  13. Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies?
  14. Paracrine regulations of IFN-γ secreting CD4 + T cells by lumican and biglycan are protective in allergic contact dermatitis.
  15. Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.
  16. The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.
  1. bioRxiv. 2024 Oct 14. pii: 2024.10.10.617261. [Epub ahead of print]
    Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
    Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.
      Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8+ T cell responses in vivo.
    Keywords:  CD8+ T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism
    DOI:  https://doi.org/10.1101/2024.10.10.617261
  2. Oncogene. 2024 Oct 29.
    Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
    Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes.
      Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
    DOI:  https://doi.org/10.1038/s41388-024-03191-1
  3. Curr Opin Immunol. 2024 Oct 25. pii: S0952-7915(24)00088-8. [Epub ahead of print]91 102498
    The immunometabolic roots of aging.
    Pierpaolo Ginefra, Helen C Hope, Girieca Lorusso, Patrizia D'Amelio, Nicola Vannini.
      Aging is one of the greatest risk factors for several chronic diseases and is accompanied by a progressive decline of cellular and organ function. Recent studies have highlighted the changes in metabolism as one of the main drivers of organism dysfunctions during aging and how that strongly deteriorate immune cell performance and function. Indeed, a dysfunctional immune system has been shown to have a pleiotropic impact on the organism, accelerating the overall aging process of an individual. Intrinsic and extrinsic factors are responsible for such metabolic alterations. Understanding the contribution, regulation, and connection of these different factors is fundamental to comprehend the process of aging and develop approaches to mitigate age-related immune decline. Here, we describe metabolic perturbations occurring at cellular and systemic levels. Particularly, we emphasize the interplay between metabolism and immunosenescence and describe novel interventions to protect immune function and promote health span.
    DOI:  https://doi.org/10.1016/j.coi.2024.102498
  4. Int Immunopharmacol. 2024 Oct 24. pii: S1567-5769(24)01934-9. [Epub ahead of print]143(Pt 2): 113412
    Targeting metabolic pathway enhance CAR-T potency for solid tumor.
    Wenying Li, Jiannan Chen, Zhigang Guo.
      Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy.
    Keywords:  CAR-T cell therapy; Immunotherapy; Metabolism reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113412
  5. Front Aging. 2024 ;5 1490302
    The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.
    Marianna V Wrona, Rituparna Ghosh, Kaitlyn Coll, Connor Chun, Matthew J Yousefzadeh.
      As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals.
    Keywords:  cellular senescence; immune resilience; immunosenescence; inflammaging; inflammation
    DOI:  https://doi.org/10.3389/fragi.2024.1490302
  6. Biomedicines. 2024 Oct 03. pii: 2250. [Epub ahead of print]12(10):
    Development of a Competitive Nutrient-Based T-Cell Immunotherapy Designed to Block the Adaptive Warburg Effect in Acute Myeloid Leukemia.
    Huynh Cao, Jeffrey Xiao, David J Baylink, Vinh Nguyen, Nathan Shim, Jae Lee, Dave J R Mallari, Samiksha Wasnik, Saied Mirshahidi, Chien-Shing Chen, Hisham Abdel-Azim, Mark E Reeves, Yi Xu.
      Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., glucose) from T cells, leading to T-cell dysfunction and leukemia progression. Methods: Thus, we explored whether genetic reprogramming of T-cell metabolism could improve their survival and empower T cells with a competitive glucose-uptake advantage against blasts and inhibit their uncontrolled proliferation. Results: Here, we discovered that high-glucose concentration reduced the T-cell expression of glucose transporter GLUT1 (SLC2A1) and TFAM (mitochondrion transcription factor A), an essential transcriptional regulator of mitochondrial biogenesis, leading to their impaired expansion ex vivo. To overcome the glucose-induced genetic deficiency in metabolism, we engineered T cells with lentiviral overexpression of SLC2A1 and/or TFAM transgene. Multi-omics analyses revealed that metabolic reprogramming promoted T-cell proliferation by increasing IL-2 release and reducing exhaustion. Moreover, the engineered T cells competitively deprived glucose from allogenic blasts and lessened leukemia burden in vitro. Conclusions: Our findings propose a novel T-cell immunotherapy that utilizes a dual strategy of starving blasts and cytotoxicity for preventing uncontrolled leukemia proliferation.
    Keywords:  AML; CAR T; GLUT1; T cells; TFAM; Warburg effect; glucose; immunotherapy; mitochondrion; nutrient
    DOI:  https://doi.org/10.3390/biomedicines12102250
  7. Nat Immunol. 2024 Nov;25(11): 1979
    How to feed mitochondria to T cells.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-024-02008-3
  8. Nat Commun. 2024 Oct 30. 15(1): 9388
    N-acetyltransferase 10 is implicated in the pathogenesis of cycling T cell-mediated autoimmune and inflammatory disorders in mice.
    Wen-Ping Li, Xin-Tao Mao, Jia-Huan Xie, Jie-Yu Li, Bao-Qin Liu, Le-Xi Wu, Bing Yang, Yi-Yuan Li, Jin Jin.
      T cell expansion has a crucial function in both autoimmune and chronic inflammatory diseases, with cycling T cells contributing to the pathogenesis of autoimmune diseases by causing uncontrolled immune responses and tissue damage. Yet the regulatory mechanisms governing T cell expansion remain incompletely understood. Here we show that the enzyme N-acetyltransferase 10 (NAT10) regulates T cell activation and proliferation upon antigen stimulation. T cell-specific NAT10 deficiency in mice reduces the number of mature T cells in peripheral lymphoid organs. Mechanistically, NAT10 acetylates RACK1 at K185, preventing subsequent RACK1 K48-linked ubiquitination and degradation. The increased RACK1 stability alters ribosome formation and cellular metabolism, leading to enhanced supply of energy and biosynthetic precursors and, eventually, T cell proliferation. Our findings thus highlight the essential function of NAT10 in T cell self-renewal and metabolism and elucidate NAT10 mode of action for the potential development of novel therapies for immune-related disorders.
    DOI:  https://doi.org/10.1038/s41467-024-53350-x
  9. Mol Ther Nucleic Acids. 2024 Dec 10. 35(4): 102350
    Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer.
    Angela L Hughson, Gary Hannon, Noah A Salama, Tara G Vrooman, Caroline A Stockwell, Bradley N Mills, Jesse Garrett-Larsen, Haoming Qiu, Roula Katerji, Lauren Benoodt, Carl J Johnston, Joseph D Murphy, Emma Kruger, Jian Ye, Nicholas W Gavras, David C Keeley, Shuyang S Qin, Maggie L Lesch, Jason B Muhitch, Tanzy M T Love, Laura M Calvi, Edith M Lord, Nadia Luheshi, Jim Elyes, David C Linehan, Scott A Gerber.
      Pronounced T cell exhaustion characterizes immunosuppressive tumors, with the tumor microenvironment (TME) employing multiple mechanisms to elicit this suppression. Traditional immunotherapies, such as immune checkpoint blockade, often fail due to their focus primarily on T cells. To overcome this, we utilized a proinflammatory cytokine, interleukin (IL)-12, that re-wires the immunosuppressive TME by inducing T cell effector function while also repolarizing immunosuppressive myeloid cells. Due to toxicities observed with systemic administration of this cytokine, we utilized lipid nanoparticles encapsulating mRNA encoding IL-12 for intratumoral injection. This strategy has been proven safe and tolerable in early clinical trials for solid malignancies. We report an unprecedented loss of exhausted T cells and the emergence of an activated phenotype in murine pancreatic ductal adenocarcinoma (PDAC) treated with stereotactic body radiation therapy (SBRT) and IL-12mRNA. Our mechanistic findings reveal that each treatment modality contributes to the T cell response differently, with SBRT expanding the T cell receptor repertoire and IL-12mRNA promoting robust T cell proliferation and effector status. This distinctive T cell signature mediated marked growth reductions and long-term survival in local and metastatic PDAC models. This is the first study of its kind combining SBRT with IL-12mRNA and provides a promising new approach for treating this aggressive malignancy.
    Keywords:  IL-12; MT: Delivery Strategies; T cell immunity; antitumor immune response; lipid nanoparticles; mRNA; pancreatic cancer; stereotactic body radiation therapy
    DOI:  https://doi.org/10.1016/j.omtn.2024.102350
  10. Nat Metab. 2024 Oct 28.
    TrkB signalling regulates dopamine circuits and motor function through metabolic pathways.
      
    DOI:  https://doi.org/10.1038/s42255-024-01154-0
  11. Nat Immunol. 2024 Nov;25(11): 1979
    Dosage compensation in T cells.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-024-02012-7
  12. Immun Ageing. 2024 Oct 29. 21(1): 75
    Age-dependent immune profile in healthy individuals: an original study, systematic review and meta-analysis.
    Syuan-Ting Chang, Yi-Fang Chuang, Ai-Hsien Li, Yang-Teng Fan, Man-Ru Liao, I-Yu Chen, Ruo-Wei Hung, Tienyu Owen Yang, Yen-Ling Chiu.
       BACKGROUND: The circulatory peripheral immune system is the most convenient approach for determining an individual's immune status. Due to various reasons, while previous studies have addressed the critical impact of age, most individual studies did not analyze immunosenescence in a systemic manner, which complicates the possibility of building a reference range for age-dependent immune profiles for effective immune monitoring. To address this gap, this study analyzed a group of healthy individuals to establish age-specific reference ranges of the healthy circulatory immune profile, and a systematic review and meta-analysis were conducted to validate the findings and create generalizable immune cell reference ranges.
    RESULTS: Our study recruited a total of 363 healthy Taiwanese adults (median age 42 years [IQR 30, 62], age range 21 to 87 years, 43.3% male), including 158 under 40 years old, 127 between 40-64 years old, and 78 over 64 years old. Significant age-related alterations were observed in both adaptive and innate immune cell subsets. CD8 + T cells decreased and CD4/CD8 ratio increased, with notable increases in NK cells. CD4 + T cells were less impacted by aging, while CD8 + T cells significantly lost CD28 and increased CD31 expression with age. A clear reverse trend in naïve and memory subsets of CD4 + and CD8 + T cells was observed. Detailed reference ranges for immune cell subsets in healthy Taiwanese adults were established. A systematic review included 7,425 adults and a meta-analysis of 12 eligible studies confirmed our findings in Taiwan, enhancing generalizability.
    CONCLUSIONS: Combined with previous studies and original data through a systematic review and meta-analysis, we highlighted and quantified significant immune profile differences between older and younger individuals. The sex and age-specific reference ranges for peripheral immune cell subsets can serve as a basis for effective immune monitoring of various aging-related illnesses.
    Keywords:  Aging; Flow cytometry; Immunosenescence; Lymphocytes; Reference range
    DOI:  https://doi.org/10.1186/s12979-024-00480-x
  13. Cancer Cell Int. 2024 Oct 27. 24(1): 355
    Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies?
    Milad Taghizadeh Anvar, Kimiya Rashidan, Nima Arsam, Ashkan Rasouli-Saravani, Hamidreza Yadegari, Ali Ahmadi, Zeynab Asgari, Ahmad Ghorbani Vanan, Farid Ghorbaninezhad, Safa Tahmasebi.
      T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.
    Keywords:  Anti-tumor activity; Cancer milieu; Immunosuppression; Plasticity; Th17 cells
    DOI:  https://doi.org/10.1186/s12935-024-03525-9
  14. bioRxiv. 2024 Oct 23. pii: 2024.10.20.619307. [Epub ahead of print]
    Paracrine regulations of IFN-γ secreting CD4 + T cells by lumican and biglycan are protective in allergic contact dermatitis.
    George Maiti, Jihane Frikeche, Cynthia Loomis, Shukti Chakravarti.
      The extracellular matrix (ECM) is known to regulate innate immune cells but its role in T cell functions is poorly understood. Here, we show a protective role for ECM proteoglycans, lumican and biglycan in hapten-induced contact dermatitis that is achieved through limiting proinflammatory CD4 + T cells. Lumican and biglycan-null mice develop significant inflammation with greater numbers of CD4 + T cells in hapten-challenged ear pinnae, while their draining lymph nodes show increased T-bet-STAT1 signaling, Th1 commitment, and IFN-γ secreting CD4 + T cell proliferation. Wild type mouse lymph node fibroblastic reticular cells secrete lumican, biglycan and decorin, a related proteoglycan, while none are expressed by naive or activated T cells. In vitro , lumican and biglycan co-localize with LFA-1 on T cell surfaces, and all three proteoglycans suppress LFA-1 mediated T cell activation. Overall, this study elucidates a novel paracrine regulation of Th1 cells by ECM proteoglycans to limit inflammation and tissue damage.
    DOI:  https://doi.org/10.1101/2024.10.20.619307
  15. Cell Death Dis. 2024 Oct 26. 15(10): 775
    Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.
    Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui.
      The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.
    DOI:  https://doi.org/10.1038/s41419-024-07122-6
  16. Commun Biol. 2024 Oct 31. 7(1): 1422
    The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.
    Chiemela Ohanele, Jessica N Peoples, Anja Karlstaedt, Joshua T Geiger, Ashley D Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E Brown, Michael E Davis, George A Porter, Victor Faundez, Jennifer Q Kwong.
      The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease.
    DOI:  https://doi.org/10.1038/s42003-024-07110-8
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