bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–06–04
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Transcriptome-based measurement of CD8+ T cell age and its applications.
  2. Localization, tissue biology and T cell state - implications for cancer immunotherapy.
  3. Immunogenetic metabolomics reveals key enzymes that modulate CAR T-cell metabolism and function.
  4. Modulation of T cells by tryptophan metabolites in the kynurenine pathway.
  5. Orchestral role of lipid metabolic reprogramming in T-cell malignancy.
  6. T-cell senescence induced by peripheral phospholipids.
  7. Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.
  8. Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis.
  9. Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.
  10. Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
  11. Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
  12. Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases.
  13. The ageing immune system as a potential target of senolytics.
  1. Trends Immunol. 2023 May 27. pii: S1471-4906(23)00098-4. [Epub ahead of print]
    Transcriptome-based measurement of CD8+ T cell age and its applications.
    Nan-Ping Weng.
      The ability of T cells to undergo robust cell division in response to antigenic stimulation is essential for competent T cell function. However, this ability is reduced with aging and contributes to increased susceptibility to infectious diseases, cancers, and other diseases among older adults. To better understand T cell aging, improved measurements of age-related cellular changes in T cells are necessary. The recent development of machine learning (ML)-assisted transcriptome-based quantification of individual CD8+ T cell age represents a significant step forward in this regard. It reveals both prominent and subtle changes in gene expression and points to potential functional alterations of CD8+ T cells with aging. I argue that single-cell transcriptome-based age prediction in the immune system may have promising future applications.
    Keywords:  DNA methylation; T cell aging; machine learning; somatic mutation; telomere; transcriptome
    DOI:  https://doi.org/10.1016/j.it.2023.05.005
  2. Nat Rev Immunol. 2023 May 30.
    Localization, tissue biology and T cell state - implications for cancer immunotherapy.
    Jason M Schenkel, Kristen E Pauken.
      Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41577-023-00884-8
  3. Cancer Immunol Res. 2023 May 30. pii: CIR-22-0565. [Epub ahead of print]
    Immunogenetic metabolomics reveals key enzymes that modulate CAR T-cell metabolism and function.
    Paul Renauer, Jonathan J Park, Meizhu Bai, Arianny Acosta, Won-Ho Lee, Guang Han Lin, Yueqi Zhang, Xiaoyun Dai, Guangchuan Wang, Youssef Errami, Terence Wu, Paul Clark, Lupeng Ye, Quanjun Yang, Sidi Chen.
      Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric-antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunological analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0565
  4. Trends Pharmacol Sci. 2023 May 27. pii: S0165-6147(23)00089-5. [Epub ahead of print]
    Modulation of T cells by tryptophan metabolites in the kynurenine pathway.
    Trevor W Stone, Richard O Williams.
      Lymphocytes maturing in the thymus (T cells) are key factors in adaptive immunity and the regulation of inflammation. The kynurenine pathway of tryptophan metabolism includes several enzymes and compounds that can modulate T cell function, but manipulating these pharmacologically has not achieved the expected therapeutic activity for the treatment of autoimmune disorders and cancer. With increasing knowledge of other pathways interacting with kynurenines, the expansion of screening methods, and the application of virtual techniques to understanding enzyme structures and mechanisms, details of interactions between kynurenines and other pathways are being revealed. This review surveys some of these alternative approaches to influence T cell function indirectly via the kynurenine pathway and summarizes the most recent work on the development of compounds acting directly on the kynurenine pathway.
    Keywords:  3-hydroxyanthranilic acid; AHR; GPR35; IDO; IL4i1; T cells; autoimmunity; cancer therapy; immune tolerance; indoleamine 2,3-dioxygenase; kynurenic acid; kynurenine; tryptophan
    DOI:  https://doi.org/10.1016/j.tips.2023.04.006
  5. Front Oncol. 2023 ;13 1122789
    Orchestral role of lipid metabolic reprogramming in T-cell malignancy.
    Arundhati Mehta, Yashwant Kumar Ratre, Vivek Kumar Soni, Dhananjay Shukla, Subhash C Sonkar, Ajay Kumar, Naveen Kumar Vishvakarma.
      The immune function of normal T cells partially depends on the maneuvering of lipid metabolism through various stages and subsets. Interestingly, T-cell malignancies also reprogram their lipid metabolism to fulfill bioenergetic demand for rapid division. The rewiring of lipid metabolism in T-cell malignancies not only provides survival benefits but also contributes to their stemness, invasion, metastasis, and angiogenesis. Owing to distinctive lipid metabolic programming in T-cell cancer, quantitative, qualitative, and spatial enrichment of specific lipid molecules occur. The formation of lipid rafts rich in cholesterol confers physical strength and sustains survival signals. The accumulation of lipids through de novo synthesis and uptake of free lipids contribute to the bioenergetic reserve required for robust demand during migration and metastasis. Lipid storage in cells leads to the formation of specialized structures known as lipid droplets. The inimitable changes in fatty acid synthesis (FAS) and fatty acid oxidation (FAO) are in dynamic balance in T-cell malignancies. FAO fuels the molecular pumps causing chemoresistance, while FAS offers structural and signaling lipids for rapid division. Lipid metabolism in T-cell cancer provides molecules having immunosuppressive abilities. Moreover, the distinctive composition of membrane lipids has implications for immune evasion by malignant cells of T-cell origin. Lipid droplets and lipid rafts are contributors to maintaining hallmarks of cancer in malignancies of T cells. In preclinical settings, molecular targeting of lipid metabolism in T-cell cancer potentiates the antitumor immunity and chemotherapeutic response. Thus, the direct and adjunct benefit of lipid metabolic targeting is expected to improve the clinical management of T-cell malignancies.
    Keywords:  T cell malignancies; fatty acids; lipid droplets; lipid metabolism; lipid rafts
    DOI:  https://doi.org/10.3389/fonc.2023.1122789
  6. Cell Biol Toxicol. 2023 Jun 01.
    T-cell senescence induced by peripheral phospholipids.
    Mingyue Ma, Ying Yang, Zhouyi Chen, Xiaoyan Li, Zhicheng Yang, Ke Wang, Xusuo Li, Hao Fang, Yunfeng Cheng, Tiankui Qiao, Xin Zou, Zhiqiang Lu, Xiangdong Wang, Duojiao Wu.
      We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting. • The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids; • The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.
    Keywords:  Immune senescence; Metabolism; Phospholipid; T cell; Tumor
    DOI:  https://doi.org/10.1007/s10565-023-09811-y
  7. Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00594-6. [Epub ahead of print]42(6): 112583
    Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.
    Enric Mocholi, Laura Russo, Keshav Gopal, Andrew G Ramstead, Sophia M Hochrein, Harmjan R Vos, Geert Geeven, Adeolu O Adegoke, Anna Hoekstra, Robert M van Es, Jose Ramos Pittol, Sebastian Vastert, Jared Rutter, Timothy Radstake, Jorg van Loosdregt, Celia Berkers, Michal Mokry, Colin C Anderson, Ryan M O'Connell, Martin Vaeth, John Ussher, Boudewijn M T Burgering, Paul J Coffer.
      Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.
    Keywords:  CP: Metabolism; T cell; citrate; epigenetics; epigenome remodeling; glucose metabolism; glycolysis; histone acetylation; nuclear metabolism; pyruvate; pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112583
  8. Blood. 2023 May 30. pii: blood.2022018303. [Epub ahead of print]
    Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis.
    Sevgi Kostel Bal, Sarah Giuliani, Jana Block, Peter Repiscak, Christoph Hafemeister, Tala Shahin, Nurhan Kasap, Bernhard Ransmayr, Yirun Miao, Cheryl van de Wetering, Alexandra Frohne, Raul Jimenez-Heredia, Michael K Schuster, Samaneh Zoghi, Vanessa Hertlein, Marini Thian, Aleksandr Bykov, Royala Babayeva, Sevgi Bilgic Eltan, Elif Karakoc-Aydiner, Lisa E Shaw, Iftekhar Chowdury, Markku Varjosalo, Rafael Jose Argüello, Matthias Farlik, Ahmet Ozen, Edgar Albert Ernst Serfling, Loïc Dupré, Christoph Bock, Florian Halbritter, J Thomas Hannich, Irinka Castanon, Michael J Kraakman, Safa Baris, Kaan Boztug.
      The NFAT family of transcription factors plays central roles in adaptive immunity in murine models, however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified three patients carrying germline biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia and decreased antibody responses. The compound heterozygous NFATC1 variants identified in the patients caused decreased stability and reduced binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to reconstitution upon genetic rescue. Following stimulation, T-cell activation and proliferation were impaired, reaching that of healthy controls with delay indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells, revealed that NFATc1-dysfunction rendered T cells unable to engage in glycolysis following stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost activation responses. Indeed, we observed increased 13C-labelled palmitate incorporation into citrate indicating higher fatty acid oxidation and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, and reveal evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells to remedy delayed effector responses.
    DOI:  https://doi.org/10.1182/blood.2022018303
  9. Nat Commun. 2023 Jun 02. 14(1): 3208
    Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.
    Xu Feng, Liwen Wang, Ruoyu Zhou, Rui Zhou, Linyun Chen, Hui Peng, Yan Huang, Qi Guo, Xianghang Luo, Haiyan Zhou.
      Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-023-38842-6
  10. Cancer Cell. 2023 May 22. pii: S1535-6108(23)00180-0. [Epub ahead of print]
    Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
    Adriano B Chaves-Filho, Almut Schulze.
      Cholesterol is essential for the ability of cytotoxic T cells to eliminate cancer cells. In this issue of Cancer Cell, Yan et al. reveal how intra-tumoral cholesterol deficiency contributes to T cell exhaustion by inhibiting mTORC1 signaling. Moreover, they demonstrate that increasing cholesterol levels in chimeric antigen receptor (CAR)-T cells by blocking liver X receptor (LXR) leads to improved anti-tumor function.
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.013
  11. Nat Cancer. 2023 May 29.
    Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
    Pravat Kumar Parida, Mauricio Marquez-Palencia, Suvranil Ghosh, Nitin Khandelwal, Kangsan Kim, Vidhya Nair, Xiao-Zheng Liu, Hieu S Vu, Lauren G Zacharias, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Jeffrey G McDonald, Andrew Lemoff, Yan Peng, Cheryl Lewis, Gonçalo Vale, Nils Halberg, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.
      Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.
    DOI:  https://doi.org/10.1038/s43018-023-00563-6
  12. Neurosci Bull. 2023 May 31.
    Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases.
    Feifei Li, Chou Wu, Gelin Wang.
      As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.
    Keywords:  Ageing; NAD metabolism; Neurodegenerative diseases; Neuroprotection; Therapeutic strategy
    DOI:  https://doi.org/10.1007/s12264-023-01072-3
  13. Oxf Open Immunol. 2023 ;4(1): iqad004
    The ageing immune system as a potential target of senolytics.
    Peter Yandi Du, Ankesh Gandhi, Manraj Bawa, Justyna Gromala.
      Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.
    Keywords:  ageing; immune system; senescence; senolytic; therapy
    DOI:  https://doi.org/10.1093/oxfimm/iqad004
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