bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–12–22
eightteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
  2. Checkpoint blockade regulates T cell fate by supporting co-stimulation.
  3. TOX Does Not Drive Sepsis-Induced T-Cell Exhaustion.
  4. Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
  5. How could histotripsy change cancer immunotherapy?
  6. Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immunotherapy in melanoma patients.
  7. Too old for healthy aging? Exploring age limits of longevity treatments.
  8. PAG orchestrates T cell immune synapse function by binding to actin.
  9. Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.
  10. Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
  11. Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
  12. Identification of a Highly Functional Effector CD8 + T Cell Program after Transplantation in Mice and Humans.
  13. Immune aging and infectious diseases.
  14. T cells lead the charge against solid tumors.
  15. Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
  16. Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.
  17. Mapping mitochondrial aging.
  18. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
  1. Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244
    Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
    Bing Feng, Rongrong Li, Weilin Li, Li Tang.
      Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
    Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering
    DOI:  https://doi.org/10.1016/j.cels.2024.11.010
  2. Nat Cancer. 2024 Dec 16.
    Checkpoint blockade regulates T cell fate by supporting co-stimulation.
      
    DOI:  https://doi.org/10.1038/s43018-024-00871-5
  3. Eur J Immunol. 2024 Dec 15. e202451395
    TOX Does Not Drive Sepsis-Induced T-Cell Exhaustion.
    Yingyu Qin, Yilin Qian, Shengqiu Liu, Rong Chen.
      The immune system undergoes profound dysregulation in sepsis, characterized by hyperinflammation in the acute phase followed by long-lasting immunosuppression. T-cell exhaustion has been proposed as one facet of sepsis-related immunosuppression, which is characterized by impaired effector function and continuous expression of PD1. However, the current analysis of T-cell exhaustion in the post-sepsis is inadequate. Our current study has identified a progressive increase in the frequency of CD44+CD11a+ memory T cells during the post-sepsis phase, accompanied by the upregulation of exhaustion markers (PD-1, Lag3, and Tim3) and functional impairments in these cells. TOX is traditionally recognized as a key regulator driving CD8+ T-cell exhaustion in cancer and chronic infection. However, we demonstrate that TOX does not play a critical role in T-cell exhaustion during chronic sepsis but rather is involved in T-cell effector function. Both knockout and "knockdown" of TOX failed to alleviate sepsis-induced T-cell exhaustion. Instead, deletion of TOX impaired the effector function of T cells in chronic sepsis, contradicting its impact on short-term TCR engagement. Our study provides a novel insight into sepsis-induced T-cell exhaustion, highlighting the distinct characteristics of T-cell exhaustion programmed by sepsis.
    Keywords:  TOX; T‐cell exhaustion; memory; sepsis
    DOI:  https://doi.org/10.1002/eji.202451395
  4. Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]
    Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
    Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.
      Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-5278203/v1
  5. Immunotherapy. 2024 Dec 18. 1-3
    How could histotripsy change cancer immunotherapy?
    Heineken Queen, Clifford S Cho.
      
    Keywords:  Histotripsy; T cell; abscopal; cancer; immunology; immunotherapy; ultrasound
    DOI:  https://doi.org/10.1080/1750743X.2024.2442899
  6. PNAS Nexus. 2024 Dec;3(12): pgae539
    Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immunotherapy in melanoma patients.
    Giuseppe Giuliani, William Stewart, Zihai Li, Ciriyam Jayaprakash, Jayajit Das.
      High-dimensional, spatial single-cell technologies, such as CyTOF imaging mass cytometry (IMC), provide detailed information regarding locations of a large variety of cancer and immune cells in microscopic scales in tumor microarray slides obtained from patients prior to immune checkpoint inhibitor (ICI) therapy. An important question is how the initial spatial organization of these cells in the tumor microenvironment (TME) changes with time and regulates tumor growth and eventually outcomes as patients undergo ICI therapy. Utilizing IMC data of melanomas of patients who later underwent ICI therapy, we develop a spatially resolved interacting cell system model that is calibrated against patient response data to address the above question. We find that the tumor fate in these patients is determined by the spatial organization of activated CD8+ T cells, macrophages, and melanoma cells and the interplay between these cells that regulate exhaustion of CD8+ T cells. We find that fencing of tumor cell boundaries by exhausted CD8+ T cells is dynamically generated from the initial conditions that can play a protumor role. Furthermore, we find that specific spatial features such as co-clustering of activated CD8+ T cells and macrophages in the pretreatment samples determine the fate of the tumor progression, despite stochastic fluctuations and changes over the treatment course. Our framework enables the determination of mechanisms of interplay between a key subset of tumor and immune cells in the TME that regulate clinical response to ICIs.
    Keywords:  imaging mass cytometry; mechanistic modeling; melanoma; stochastic fluctuations
    DOI:  https://doi.org/10.1093/pnasnexus/pgae539
  7. NPJ Metab Health Dis. 2024 ;2(1): 37
    Too old for healthy aging? Exploring age limits of longevity treatments.
    Prerana Shrikant Chaudhari, Maria A Ermolaeva.
      It is well documented that aging elicits metabolic failures, while poor metabolism contributes to accelerated aging. Metabolism in general, and energy metabolism in particular are also effective entry points for interventions that extend lifespan and improve organ function during aging. In this review, we discuss common metabolic remedies for healthy aging from the angle of their potential age-specificity. We demonstrate that some well-known metabolic treatments are mostly effective in young and middle-aged organisms, while others maintain high efficacy independently of age. The mechanistic basis of presence or lack of the age limitations is laid out and discussed.
    Keywords:  Energy metabolism; Metabolism; Mitochondria; Physiology
    DOI:  https://doi.org/10.1038/s44324-024-00040-3
  8. bioRxiv. 2024 Dec 03. pii: 2024.11.29.625440. [Epub ahead of print]
    PAG orchestrates T cell immune synapse function by binding to actin.
    Emily K Moore, Marianne Strazza, Xizi Hu, Carly Tymm, Matthieu Paiola, Michael J Shannon, Xinping Xie, Shoiab Bukhari, Shalom Lerrer, Emily M Mace, Robert Winchester, Adam Mor.
      Many immunotherapies impact T cell function by impacting the immune synapse. While immunotherapy is extremely successful in some patients, in many others, it fails to help or causes complications, including immune-related adverse events. Phosphoprotein Associated with Glycosphingolipid Rich Microdomains 1 (PAG) is a transmembrane scaffold protein with importance in T cell signaling. PAG has 10 tyrosine phosphorylation sites where many kinases and phosphatases bind. PAG is palmitoylated, so it localizes in lipid rafts of the membrane, and contains a C-terminal PDZ domain to link to the actin cytoskeleton. As a link between signaling-protein-rich membrane regions and the actin cytoskeleton, PAG is an exciting and novel target for manipulating immune function. Here, we sought to determine if PAG works with actin to control T cell synapse organization and function. We found that PAG and actin dynamics are tightly coordinated during synapse maturation. A PDZ domain mutation disrupts the PAG-actin interaction, significantly impairing synapse formation, stability, and function. To assess the impact of the PDZ mutation functionally in vivo, we employed a mouse model of type IV hypersensitivity and an OVA-tumor mouse model. In both systems, mice with T cells expressing PDZ-mutant PAG had diminished immune responses, including impaired cytotoxic function. These findings highlight the importance of the PAG-actin link for effective T cell immune synapse formation and function. The results of our study suggest that targeting PAG is a promising approach for modulating immune responses and treating immune-related diseases.
    One Sentence Summary: Adaptor protein PAG links to the actin cytoskeleton, and this link is essential for T cell synapse formation and cytotoxic function.
    DOI:  https://doi.org/10.1101/2024.11.29.625440
  9. Curr Opin Immunol. 2024 Dec 12. pii: S0952-7915(24)00101-8. [Epub ahead of print]92 102511
    Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.
    Janika Härm, Yu-Tong Fan, Dirk Brenner.
      Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, playing crucial roles in modulating autoimmune conditions and contributing to the suppressive tumor microenvironment. Their cellular metabolism governs their generation, stability, proliferation, and suppressive function. Enhancing Treg metabolism to boost their suppressive function offers promising therapeutic potential for alleviating inflammatory symptoms in autoimmune diseases. Conversely, inhibiting Treg metabolism to reduce their suppressive function can enhance the efficacy of traditional immunotherapy in cancer patients. This review explores recent advances in targeting Treg metabolism in autoimmune diseases and the metabolic adaptations of Tregs within the tumor microenvironment that increase their immunosuppressive function.
    DOI:  https://doi.org/10.1016/j.coi.2024.102511
  10. Biochim Biophys Acta Mol Basis Dis. 2024 Dec 15. pii: S0925-4439(24)00623-9. [Epub ahead of print]1871(3): 167629
    Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
    Yi-Jia-Ning Zhang, Yao Xiao, Zi-Zhan Li, Lin-Lin Bu.
      Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.
    Keywords:  Head and neck squamous cell carcinoma; Immunometabolism; Immunotherapy; Prognosis
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167629
  11. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2412070121
    Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
    Heng Wang, Fang Xu, Chenlu Yao, Huaxing Dai, Jialu Xu, Bingbing Wu, Bo Tian, Xiaolin Shi, Chao Wang.
      Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan-expressing Clostridium butyricum (L-Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L-Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L-Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L-Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.
    Keywords:  IDO; T cell response; engineering bacteria; synthetic biology; tryptophan
    DOI:  https://doi.org/10.1073/pnas.2412070121
  12. bioRxiv. 2024 Dec 02. pii: 2024.11.26.625263. [Epub ahead of print]
    Identification of a Highly Functional Effector CD8 + T Cell Program after Transplantation in Mice and Humans.
    Gregory S Cohen, Joel S Freibaum, Riley P Leathem, Ryo Hatano, Chikao Morimoto, Scott M Krummey.
      Acute T cell mediated rejection of allografts remains a significant risk factor for early graft loss. Our prior work defined a population of graft-specific CD8 + T cells positive for the activated receptor CD43 (expressing the 1B11 epitope) that form during acute rejection, leading us to further understand the in vivo fate and clinical relevance of this population. We found that during acute rejection, the CD43 + ICOS + phenotype was sensitive for proliferative graft-specific CD8 + T cells. We evaluated whether CD43 1B11 signaling could impact graft survival, and found that CD43 1B11 mAb treatment could overcome costimulation-blockade induced tolerance in the majority of mice. Using an adoptive transfer approach, we investigated the fate of CD43 1B11 + and CD43 1B11 - CD8 + T cell populations, and found that CD43 1B11 + CD8 + T cells were more persistent three weeks after transplantation. A portion of CD43 1B11 - CD8 + T cells converted to CD43 1B11 + , while CD43 1B11 + CD8 + T cells retained CD43 1B11 + status. In healthy human donors, we found that the CD43 1D4 clone, which identifies the large CD43 isoform, defines a population of antigen-experienced CD8 + T cells independent of the canonical CD8 + T cell populations. CD43 1D4 + CD8 + T cells were efficient cytokine-producers after stimulation. In scRNA-seq analysis of graft-infiltrating cells from renal transplant patients experiencing acute rejection, a population of SPN + GCNT1 + CD8 + T cells had an effector phenotype that includes high expression of IFNG, ICOS, and perforins/granzymes. Together, these data provide evidence that the CD43 1B11 expression defines a proliferative and persistent population of CD8 + T cells in mice, and that an analogous population of antigen-experienced CD8 + T cells that participate in allograft rejection.
    DOI:  https://doi.org/10.1101/2024.11.26.625263
  13. Chin Med J (Engl). 2024 Dec 16.
    Immune aging and infectious diseases.
    Ruochan Chen, Ju Zou, Jiawang Chen, Ling Wang, Rui Kang, Daolin Tang.
       ABSTRACT: The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.
    DOI:  https://doi.org/10.1097/CM9.0000000000003410
  14. Nat Cancer. 2024 Dec 17.
    T cells lead the charge against solid tumors.
    Rigel J Kishton, Nicholas P Restifo.
      
    DOI:  https://doi.org/10.1038/s43018-024-00860-8
  15. Cell Mol Biol Lett. 2024 Dec 18. 29(1): 153
    Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
    Meng Zhang, Jin Wei, Chang He, Liutao Sui, Chucheng Jiao, Xiaoyan Zhu, Xudong Pan.
      Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.
    Keywords:  Age-related diseases; Aging; Mitochondrial communication; Mitochondrial dysfunction; Signaling hubs
    DOI:  https://doi.org/10.1186/s11658-024-00669-4
  16. PLoS Biol. 2024 Dec 17. 22(12): e3002943
    Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.
    Matthew L Lawton, Melissa M Inge, Benjamin C Blum, Erika L Smith-Mahoney, Dante Bolzan, Weiwei Lin, Christina McConney, Jacob Porter, Jarrod Moore, Ahmed Youssef, Yashasvi Tharani, Xaralabos Varelas, Gerald V Denis, Wilson W Wong, Dzmitry Padhorny, Dima Kozakov, Trevor Siggers, Stefan Wuchty, Jennifer Snyder-Cappione, Andrew Emili.
      Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.
    DOI:  https://doi.org/10.1371/journal.pbio.3002943
  17. Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13
    Mapping mitochondrial aging.
    Alessandro Bitto.
      Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.
    Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.105191
  18. Nat Metab. 2024 Dec;6(12): 2319-2337
    Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
    Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.
      The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.
    DOI:  https://doi.org/10.1038/s42255-024-01174-w
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