bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–02–02
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic reprogramming in inflammaging and aging in T cells.
  2. Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
  3. Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
  4. PD-1 prelimits both the cytotoxic and exhaustion potential in thymic CD8+ T cells and impacts the maintenance of peripheral tumor immunity.
  5. Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11.
  6. tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.
  7. Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.
  8. Molecular and Cellular Mechanisms of Immunosenescence: Modulation Through Interventions and Lifestyle Changes.
  9. Epithelial cell diversity and immune remodeling in bladder cancer progression: insights from single-cell transcriptomics.
  10. Enhancing immunity during ageing by targeting interactions within the tissue environment.
  11. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  12. The role of memory T cells in type 1 diabetes: Phenotypes, mechanisms, and therapeutic implications.
  13. Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
  14. The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
  15. Engineering Resilient CAR T Cells for Immunosuppressive Environment.
  1. Life Metab. 2023 Oct;2(5): load028
    Metabolic reprogramming in inflammaging and aging in T cells.
    Alessio Bevilacqua, Ping-Chih Ho, Fabien Franco.
      Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.
    Keywords:  T cells; immunometabolism; inflammaging
    DOI:  https://doi.org/10.1093/lifemeta/load028
  2. J Inflamm Res. 2025 ;18 1091-1106
    Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
    Zhuo-Yu Zhang, Fang Wang, Gang Zhou.
       Purpose: Oral lichen planus (OLP) is a chronic, immune-mediated inflammatory disease involving T cells. Mitochondrial fission plays a crucial role in T cell fate through structural remodeling. Nicotinamide adenine dinucleotide (NAD+) regulates mitochondrial remodeling and function. This study explored the role of NAD+ in modulating mitochondrial fission and apoptosis in T cells under the OLP immune-inflammatory environment.
    Patients and Methods: T cells and plasma were isolated from peripheral blood. Mitochondrial morphology was characterized by transmission electron microscopy and Mito-Tracker staining. OLP plasma-exposed Jurkat T cells were infected with the Drp1 shRNA virus to investigate the role of mitochondrial fission in OLP T cell apoptosis. OLP T cells and OLP plasma-exposed Jurkat T cells were treated with either β-nicotinamide mononucleotide (an NAD+ synthesis precursor) or FK866 (an NAD+ synthesis inhibitor) to assess the effect of NAD+ regulation on mitochondrial remodeling and T cell apoptosis.
    Results: OLP T cells exhibited fragmented mitochondria with elevated dynamin-related protein 1 (Drp1) and reduced mitofusin 2 (Mfn2) expression, accompanied by decreased apoptosis. Drp1 knockdown in OLP plasma-exposed Jurkat T cells increased apoptosis and reduced proliferation. NAD+ levels were reduced in both OLP T cells and OLP plasma-treated Jurkat T cells, leading to enhanced mitochondrial fission, decreased mitochondrial membrane potential (MMP) and respiration function, and reduced apoptosis rate. β-nicotinamide mononucleotide supplementation restored NAD+ levels, suppressed mitochondrial fission, improved MMP, and promoted apoptosis in these cells.
    Conclusion: Reduced NAD+ levels in OLP T cells enhanced mitochondrial fission and contributed to decreased apoptosis. NAD+ supplementation mitigated these effects, suggesting a potential therapeutic strategy for restoring T cell homeostasis in OLP.
    Keywords:  T cells; mitochondria; nicotinamide adenine dinucleotide; oral lichen planus
    DOI:  https://doi.org/10.2147/JIR.S502273
  3. Cell Metab. 2025 Jan 24. pii: S1550-4131(24)00489-3. [Epub ahead of print]
    Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
    Andrew T Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B Rhodes Ford, Supriya Joshi, Katarzyna M Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A Jana, Victoria G Dean, William G Gunn, Stacy Gelhaus, Amanda C Poholek, Dayana B Rivadeneira, Greg M Delgoffe.
      Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.
    Keywords:  CAR-T; Immunometabolism; T cell; cell therapy; epigenetics; glucose; immunotherapy; longevity; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.007
  4. bioRxiv. 2025 Jan 18. pii: 2025.01.18.631253. [Epub ahead of print]
    PD-1 prelimits both the cytotoxic and exhaustion potential in thymic CD8+ T cells and impacts the maintenance of peripheral tumor immunity.
    Zhiming Mao, Jacob B Hirdler, Joanina K Gicobi, Mark Maynes, Michelle A Hsu, Emilia R Dellacecca, Wenjing Zhang, Jacob J Teske, Ying Li, Geoffrey Zhao, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau, Haidong Dong.
      Durable T cell immunity against cancer depends on the continual replenishment of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, the effector potential of thymic mature CD8+ T cells and their regulation have not been clearly defined. In this study, we identified the ability of thymic single positive CD8+ T cells to gain effector potential after thymic selection, but they are subject to the regulation of PD-1. We found a previously undisclosed role of PD-1 in limiting both the cytotoxic and exhaustion potential of thymic and peripheral CD8+ T cells. Our results show that although PD-1 inhibition facilitates the expansion of effector CD8+ T cells, effector CD8+ cells gradually lose their antitumor activity within tumor tissues due to advanced exhaustion in the absence of PD-1. Thus, although the preset effector potential in thymic mature CD8+ T cells allows them to rapidly respond to malignant cells in the periphery, PD-1, as a checkpoint, is embedded in the thymic mature CD8+ T cells after positive selection to balance their effector function from exaggeration and exhaustion. Therefore, we propose that a strategy capable of upholding the cytotoxic capacity and avoiding exhaustion of CD8+ T cells during the early stages of PD-1 inhibition therapy is needed to achieve durable antitumor immunity.
    DOI:  https://doi.org/10.1101/2025.01.18.631253
  5. Front Immunol. 2024 ;15 1509874
    Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11.
    Ling Li, Manzhi Zhao, Marjan van Meurs, Inge Brouwers-Haspels, Renske J H den Dekker, Merel E P Wilmsen, Dwin G B Grashof, Harmen J G van de Werken, Shringar Rao, Casper Rokx, Yvonne M Mueller, Peter D Katsikis.
       Introduction: Bryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.
    Methods: PBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established in vitro murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.
    Results: We found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of in vitro generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-γ production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.
    Discussion: Our data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells.
    Keywords:  HIV; IFN-γ production; MAP kinase 11; bryostatin-1; exhausted CD8+ T cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1509874
  6. J Exp Med. 2025 Mar 03. pii: e20240559. [Epub ahead of print]222(3):
    tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.
    Shan Miao, Hao Li, Xiaohan Song, Yongbo Liu, Gaoyang Wang, Chen Kan, Youqiong Ye, Ru-Juan Liu, Hua-Bing Li.
      Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of effector functions. However, the posttranscriptional mechanisms underpinning this process remain obscure. The transfer RNA (tRNA) N1-methyladenine (m1A) modification, essential for tRNA stability and protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A "writer" gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase, a key enzyme for cholesterol biosynthesis. Cholesterol supplementation rescues the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings highlight tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20240559
  7. Sci Immunol. 2025 Jan 31. 10(103): eadn1945
    Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.
    Catarina Gago da Graça, Amania A Sheikh, Dane M Newman, Lifen Wen, Sining Li, Jian Shen, Yuqi Zhang, Sarah S Gabriel, David Chisanga, Justine Seow, Annika Poch, Lisa Rausch, Minh-Hanh T Nguyen, Jayendra Singh, Chun-Hsi Su, Leonie A Cluse, Carlson Tsui, Thomas N Burn, Simone L Park, Bianca Von Scheidt, Laura K Mackay, Ajithkumar Vasanthakumar, David Bending, Wei Shi, Weiguo Cui, Jan Schröder, Ricky W Johnstone, Axel Kallies, Daniel T Utzschneider.
      Stem-like T cells are attractive immunotherapeutic targets in patients with cancer given their ability to proliferate and differentiate into effector progeny. Thus, identifying T cells with enhanced stemness and understanding their developmental requirements are of broad clinical and therapeutic interest. Here, we demonstrate that during acute infection, the transcriptional regulator inhibitor of DNA binding 3 (ID3) identifies stem-like T cells that are uniquely adapted to generate precursors of exhausted T (Tpex) cells in response to chronic infection or cancer. Expression of ID3 itself enables Tpex cells to sustain T cell responses in chronic infection or cancer, whereas loss of ID3 results in impaired maintenance of CD8 T cell immunity. Furthermore, we demonstrate that interleukin-1 (IL-1) family members, including IL-36β and IL-18, promote the generation of ID3+ T cells that mediate superior tumor control. Overall, we identify ID3 as a common denominator of stem-like T cells in both acute and chronic infections that is specifically required to sustain T cell responses to chronic stimulation.
    DOI:  https://doi.org/10.1126/sciimmunol.adn1945
  8. Biology (Basel). 2024 Dec 27. pii: 17. [Epub ahead of print]14(1):
    Molecular and Cellular Mechanisms of Immunosenescence: Modulation Through Interventions and Lifestyle Changes.
    Luca Pangrazzi, Andreas Meryk.
      Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.
    Keywords:  immunosenescence; inflammaging; interventions; oxidative stress
    DOI:  https://doi.org/10.3390/biology14010017
  9. J Transl Med. 2025 Jan 30. 23(1): 135
    Epithelial cell diversity and immune remodeling in bladder cancer progression: insights from single-cell transcriptomics.
    Jianpeng Li, Yunzhong Jiang, Minghai Ma, Lu Wang, Minxuan Jing, Zezhong Yang, Mengzhao Zhang, Ke Chen, Jinhai Fan.
       BACKGROUND: The progression of bladder cancer (BC) from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) significantly increases disease severity. Although the tumor microenvironment (TME) plays a pivotal role in this process, the heterogeneity of tumor cells and TME components remains underexplored.
    METHODS: We characterized the transcriptomes of single cells from 11 BC samples, including 4 NMIBC, 4 MIBC, and 3 adjacent normal tissues. Bulk RNA-seq data were used to validate the clinical features of characteristic cells, and protein levels of these cells were further confirmed through immunohistochemistry (IHC) and multiplex immunofluorescence.
    RESULTS: Bladder cancer progression was associated with distinct transcriptomic features in the TME. Tumor cells in MIBC displayed enhanced glycolytic activity and downregulation of chemokines and MHC-II molecules, reducing immune cell recruitment and facilitating immune evasion. This highlights glycolysis as a potential therapeutic target for disrupting tumor progression. We identified a T cell exhaustion pathway from naive CD8 + T cells (CD8 + TCF7) to terminally exhausted CD8 + STMN1 cells, with progressively declining immune surveillance. Targeting intermediate exhaustion states may restore T cell function and improve anti-tumor immunity. Macrophages polarized toward a pro-tumorigenic phenotype, while VEGFA + mast cells promoted angiogenesis in early-stage BC, suggesting their role as potential targets for therapeutic intervention in NMIBC. Furthermore, conventional dendritic cells (DCs) transformed into LAMP3 + DCs, contributing to an immunosuppressive microenvironment and enabling immune evasion.
    CONCLUSION: This study reveals dynamic changes in the TME during BC progression, including enhanced glycolysis, T cell exhaustion, and immune cell remodeling, which contribute to immune evasion and tumor progression. These findings identify critical pathways and cell populations as potential therapeutic targets, offering new strategies to improve treatment outcomes in BC patients.
    Keywords:  Epithelial cell; MIBC; Myeloid cell; NMIBC; ScRNA-seq; T cell; TME
    DOI:  https://doi.org/10.1186/s12967-025-06138-6
  10. Nat Rev Drug Discov. 2025 Jan 28.
    Enhancing immunity during ageing by targeting interactions within the tissue environment.
    Olivia V Bracken, Roel P H De Maeyer, Arne N Akbar.
      Immunity declines with age. This results in a higher risk of age-related diseases, diminished ability to respond to new infections and reduced response to vaccines. The causes of this immune dysfunction are cellular senescence, which occurs in both lymphoid and non-lymphoid tissue, and chronic, low-grade inflammation known as 'inflammageing'. In this Review article, we highlight how the processes of inflammation and senescence drive each other, leading to loss of immune function. To break this cycle, therapies are needed that target the interactions between the altered tissue environment and the immune system instead of targeting each component alone. We discuss the relative merits and drawbacks of therapies that are directed at eliminating senescent cells (senolytics) and those that inhibit inflammation (senomorphics) in the context of tissue niches. Furthermore, we discuss therapeutic strategies designed to directly boost immune cell function and improve immune surveillance in tissues.
    DOI:  https://doi.org/10.1038/s41573-024-01126-9
  11. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  12. Autoimmun Rev. 2025 Jan 27. pii: S1568-9972(25)00019-9. [Epub ahead of print] 103759
    The role of memory T cells in type 1 diabetes: Phenotypes, mechanisms, and therapeutic implications.
    Pooria Fazeli, Shiva Abolhasani, Negin Karamali, Mahsa Hajivalili, Gholamreza Daryabor, Mohammad Panji, Maryam Karimian, Maryam Hosseini.
      Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing cells in the pancreatic islets. Patients with T1D have autoreactive CD4+ and CD8+ T cells that show specific features, indicating previous exposure to self-antigens. Despite that memory T cells are vital components of the adaptive immune system, providing enduring protection against pathogens; individuals with T1D have a higher proportion of memory T cells compared to healthy individuals with naїve phenotypes. Targeting memory T cells in newly diagnosed T1D patients has shown promising results, providing evidence for the significant role of memory T cells in this disease. There are various types of memory T cells, each with unique characteristics and functions. Recent advancements in understanding the complexity and heterogeneity of T cell subpopulations have shown that T1D cannot be fully understood through simple categorization. This review aims to discuss various types of memory T cells in the immunopathogenesis of T1D, focusing on their phenotypes and frequencies, as well as epigenetic and metabolic alterations. Additionally, it will address novel immunotherapeutic approaches targeting memory T cell subsets in T1D.
    Keywords:  Memory T Cells; Memory T Follicular Helper Cells; Stem Cell-like Memory T Cells; Terminally-Differentiated T Cells; Tissue-Resident Memory T Cells; Type 1 Diabetes Mellitus
    DOI:  https://doi.org/10.1016/j.autrev.2025.103759
  13. iScience. 2025 Jan 17. 28(1): 111656
    Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
    Kevin Kiesworo, Thomas Agius, Michael R Macarthur, Martine Lambelet, Arnaud Lyon, Jing Zhang, Guillermo Turiel, Zheng Fan, Sènan d'Almeida, Korkut Uygun, Heidi Yeh, Sébastien Déglise, Katrien de Bock, Sarah J Mitchell, Alejandro Ocampo, Florent Allagnat, Alban Longchamp.
      Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
    Keywords:  Cellular physiology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111656
  14. bioRxiv. 2025 Jan 15. pii: 2025.01.15.633193. [Epub ahead of print]
    The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
    Imad Soukar, Anindita Mitra, Linh Vo, Melanie Rofoo, Miriam L Greenberg, Lori A Pile.
      Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.
    DOI:  https://doi.org/10.1101/2025.01.15.633193
  15. Mol Ther. 2025 Jan 25. pii: S1525-0016(25)00039-5. [Epub ahead of print]
    Engineering Resilient CAR T Cells for Immunosuppressive Environment.
    Malak Khalifeh, Huda Salman.
      Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site and on /off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and re-engineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.01.035
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