bims-imseme 2025-02-16 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–02–16
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors.
Mitochondrial succinate feeds T cell exhaustion in cancer.
Metabolic T-cell phenotypes - from bioenergetics to function.
Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells.
T Cell Differentiation in Autoimmune Type 1 Diabetes.
KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection.
Loss of Bach2 in T cells causes prolonged allergic inflammation through the accumulation of effector T cells and disruption of the epidermal barrier.
Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.
Lymph Node Invasion by Melanoma Cells Is Not Required for the Induction of Incomplete Differentiation by Tumor-Specific CD8+ T Cells.
Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming.
Associations of the Adaptive Immune System and Age-Related Macular Degeneration.
TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus.
CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors.
Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction.
Metabolic landscape and rewiring in normal hematopoiesis, leukemia and aging.
Potential Role of NUR77 in the Aging Retinal Pigment Epithelium and Age-Related Macular Degeneration.
TIGIT expression in extrahepatic cholangiocarcinoma and its impact on CD8 + T cell exhaustion: implications for immunotherapy.
Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo.
Restoring the supply lines: removing roadblocks to fatty acid uptake enhances T cell-driven cancer fight.
Mitigating T-Cell Mitochondrial Dysfunction in CLL to Augment CAR T-Cell Therapy: Evaluation in an Immunocompetent Model.
The TET-TDG axis in T cells and biological processes.
Dietary Natural Melanin Nanozymes Delay Aging and Ameliorate Neurodegeneration via Improving Gut Microbiota and Redox Homeostasis.

Front Immunol. 2025 ;16 1484303

Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors.

Gulfiya Kadyrzhanova, Miho Tamai, Shukla Sarkar, Rajkumar Singh Kalra, Hiroki Ishikawa.

  Age-associated defects in T cell-mediated immunity can increase the risk of cancers, but how aging influences adoptive T-cell therapy (ACT) for cancers remains unclear. Here, using a mouse model of melanoma, we demonstrate that aging diminishes anti-tumor activity of engineered CD8 T cells expressing a tumor-specific T cell receptor (CD8 TCR-T cells) in ACT for solid tumors. Aged CD8 TCR-T cells cannot control tumor growth in either young or aged mice. Aged CD8 TCR-T cells are unable to accumulate efficiently in tumors and have higher tendency to become terminally exhausted T cells with lower expression of endothelial PAS domain-containing protein 1 (Epas1) compared to young cells. Crispr-mediated ablation of Epas1 promotes terminal exhaustion of young CD8 T cells in tumors, diminishing their anti-tumor activity in young mice. Conversely, retroviral expression of Epas1 enhances anti-tumor activity of aged CD8 TCR-T cells. These findings suggest that aging-induced reduction of Epas1 expression impairs anti-tumor activity of CD8 T cells in ACT against solid tumors, which can be therapeutically improved by expression of exogenous Epas1.

Keywords:  CD8 T cells; Epas1; adoptive T-cell therapy; aging; cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1484303
Cancer Cell. 2025 Feb 10. pii: S1535-6108(25)00023-6. [Epub ahead of print]43(2): 168-170

Mitochondrial succinate feeds T cell exhaustion in cancer.

Lorenzo Galluzzi, Emma Guilbaud, Abhishek D Garg.

Mitochondrial fitness is critical for effector CD8+ T cell responses against cancer. In this issue of Cancer Cell, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2025.01.005
Am J Physiol Cell Physiol. 2025 Feb 13.

Metabolic T-cell phenotypes - from bioenergetics to function.

Nouria Jantz-Naeem, Nese Guvencli, Romy Böttcher-Loschinski, Martin Böttcher, Dimitrios Mougiakakos, Sascha Kahlfuss.

  It is well known that T cell metabolism and function are intimately linked. Metabolic reprogramming is a dynamic process that provides the necessary energy and biosynthetic precursors while actively regulating the immune response of T cells. As such, aberrations and dysfunctions in metabolic (re)programming, resulting in altered metabolic endotypes, may have an impact on disease pathology in various contexts. With the increasing demand for personalized and highly specialized medicine and immunotherapy, understanding metabolic profiles and T cell subset dependence on specific metabolites will be crucial to harness the therapeutic potential of immunometabolism and T cell bioenergetics. In this review, we dissect metabolic alterations in different T cell subsets in autoimmune and viral inflammation, T cell and non-T cell malignancies, highlighting potential anchor points for future treatment and therapeutic exploitation.

Keywords:  Autoimmunity; Cancer; Immunometabolism; T cells; Viral infection

DOI:  https://doi.org/10.1152/ajpcell.00478.2024
Eur J Microbiol Immunol (Bp). 2025 Feb 12.

Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells.

Martina Palatella, Friederike Kruse, Silke Glage, André Bleich, Marina Greweling-Pils, Jochen Huehn.

  Epigenetic modifications are critical for the regulation of CD4+ T cell differentiation and function. Previously, we identified Acyl-CoA Synthetase Bubble Gum 1 (Acsbg1), a gene involved in fatty acid metabolism, as part of an epigenetic signature that was selectively demethylated in ex vivo isolated T helper 17 (TH17) cells. However, its functional relevance for CD4+ T cells remains incompletely understood. Here, we used in vitro differentiation assays and the adoptive transfer colitis model to investigate the role of Acsbg1 in the differentiation and function of TH1, TH17, and regulatory T (Treg) cells. In vitro, Acsbg1 was expressed in both TH17 and in vitro-induced Treg (iTreg) cells, whereas TH1 cells lacked Acsbg1 expression. Accordingly, Acsbg1 deficiency resulted in impaired TH17 and iTreg differentiation, whereas TH1 differentiation was unaffected. In vivo, upon adoptive transfer of Acsbg1⁻/⁻ Tnaïve cells, immunodeficient recipient mice exhibited an exacerbated colitis, characterized by an altered balance of TH17 and Treg cells, indicating that Acsbg1 expression is essential for optimal TH17 and Treg cell differentiation and function. Our findings highlight the importance of fatty acid (FA) metabolism in maintaining immune homeostasis by regulating T cell differentiation and provide novel insights into the metabolic targeting of inflammatory diseases.

Keywords:  Acsbg1; Th17; Treg; colitis; fatty acid metabolism; mucosal immunology

DOI:  https://doi.org/10.1556/1886.2025.00003
Cold Spring Harb Perspect Med. 2025 Feb 10. pii: a041592. [Epub ahead of print]

T Cell Differentiation in Autoimmune Type 1 Diabetes.

Andrea Schietinger, Ian T McBain, Katrina M Hawley, Svetlana Miakicheva.

Type 1 diabetes (T1D) is a progressive T cell-mediated autoimmune disease that results from the breakdown of tolerance mechanisms in β-cell-specific T cells. Although CD8 T cells are primarily responsible for the destruction of insulin-producing β cells, intriguingly, HLA class II allelic polymorphisms confer the greatest genetic risk for the development of T1D, suggesting a critical role of CD4 T cells in disease initiation and progression. Many aspects of autoimmune T cell differentiation remain enigmatic, including where and how autoimmune CD8 and CD4 T cells arise, which molecular programs control autoimmune T cell differentiation, and how CD8 T cells sustain β-cell destruction in the face of persistent self-antigen encounter. In this work, we summarize our current understanding of β-cell-specific CD8 and CD4 T cell differentiation and function, the role of autoimmune stem-like progenitor CD8 T cells in initiating and sustaining disease, and molecular programs and key transcription factors associated with the diabetogenic T cell response.

DOI: https://doi.org/10.1101/cshperspect.a041592
Science. 2025 Jan 02. 387(6735): eadn2337

KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection.

Eric Fagerberg, John Attanasio, Christine Dien, Jaiveer Singh, Emily A Kessler, Leena Abdullah, Jian Shen, Brian G Hunt, Kelli A Connolly, Edward De Brouwer, Jiaming He, Nivedita R Iyer, Jessica Buck, Emily R Borr, Martina Damo, Gena G Foster, Josephine R Giles, Yina H Huang, John S Tsang, Smita Krishnaswamy, Weiguo Cui, Nikhil S Joshi.

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

DOI: https://doi.org/10.1126/science.adn2337
J Allergy Clin Immunol. 2025 Feb 07. pii: S0091-6749(25)00128-9. [Epub ahead of print]

Loss of Bach2 in T cells causes prolonged allergic inflammation through the accumulation of effector T cells and disruption of the epidermal barrier.

Miyuki Omori-Miyake, Ryosuke Kawakami, Makoto Kuwahara, Masataka Okabe, Jun Muto, Takeshi Imamura, Masakatsu Yamashita.

   BACKGROUND: Bach2 has been suggested to be a risk factor for allergic diseases in previous studies. Since type IV hypersensitivity reactions, including allergic contact dermatitis (ACD), develop through activated T cells and because the expression of Bach2 is regulated in the development and functional differentiation of T cells, the expression of Bach2 in T cells may be involved in the onset of ACD. However, the role of Bach2 in T cells during ACD development has not yet been determined.
OBJECTIVE: We investigated the role of the appropriate expression of Bach2 in T cells in the development and prolongation of ACD.
METHODS: We induced ACD in mice by repeatedly applying a hapten and analyzed the expression of Bach2 in the T cells of lesional skin or skin-draining lymph nodes (sdLNs). We performed a phenotypic analysis of the skin and/or sdLNs by comparing mice with T cells overexpressing Bach2 or with Bach2 loss to the control mice.
RESULTS: We found that Bach2lo T cells accumulated in the skin and sdLNs as ACD developed. T cell-specific Bach2 deficient mice showed more severe inflammatory responses to the hapten and had prolonged inflammation with T cells expressing higher levels of IL-13 in the skin and IFN-γ and IL-13 in the sdLNs. In contrast, the mice overexpressing Bach2 in T cells developed almost no symptom of ACD.
CONCLUSION: The appropriate expression of Bach2 in T cells may be a key factor in the resolution of ACD.

Keywords:  Bach2; T-cell; allergic contact dermatitis; eczema

DOI:  https://doi.org/10.1016/j.jaci.2025.01.036
Am J Cancer Res. 2025 ;15(1): 233-247

Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.

Minjing Zhu, Yanyan Hu, Yangjia Gu, Xuedan Lin, Xiang Jiang, Chaoju Gong, Zejun Fang.

  This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.

Keywords:  Colorectal cancer; amino acid metabolism; immune evasion; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.62347/ZSOO2247
Cancer Rep (Hoboken). 2025 Feb;8(2): e70145

Lymph Node Invasion by Melanoma Cells Is Not Required for the Induction of Incomplete Differentiation by Tumor-Specific CD8+ T Cells.

Kristian M Hargadon, Travis B Goodloe, Stephen L Woodall.

   BACKGROUND: Lymph node invasion by cancer cells is a poor prognostic factor and is often associated with anti-tumor CD8+ T cell dysfunction. In this study, we investigated the role of lymph node invasion by melanoma cells in the induction of incomplete differentiation by tumor antigen-specific CD8+ T cells.
AIMS: We aimed to determine whether lymph node invasion by melanoma cells is required for this specific form of anti-tumor CD8+ T cell dysfunction.
METHODS AND RESULTS: We assessed lymph node invasion by the B16-F1 and D5.1G4 murine melanoma cell lines and evaluated tumor antigen-specific CD8+ T cell responses to these melanomas in the context of tumor-free versus tumor-involved lymph nodes. We demonstrate that CD8+ T cells recognizing antigen from established melanomas fail to acquire effector function, regardless of whether the tumor is stable or progressive. This CD8+ T cell dysfunction arises in the context of both tumor-involved and tumor-free lymph nodes draining established melanomas.
CONCLUSIONS: Lymph node invasion by melanoma cells is not required for the induction of incomplete CD8+ T cell differentiation. These data and their implications for strategies to enhance CD8+ T cell responses against poorly immunogenic melanomas are discussed herein.

Keywords:  CD8 T cell dysfunction; cancer; lymph node invasion; melanoma; tumor immunity

DOI:  https://doi.org/10.1002/cnr2.70145
Sci Transl Med. 2025 Feb 12. 17(785): eadm7269

Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming.

Feiya Ma, Xia Liu, Yuanqin Zhang, Yan Tao, Lei Zhao, Hazar Abusalamah, Cody Huffman, R Alex Harbison, Sidharth V Puram, Yuqi Wang, Guangyong Peng.

The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made with a deeper understanding of the factors that cause T cell dysfunction within the tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report that tumor-derived extracellular vesicles (tEVs) can induce senescence and suppression in T cells. Programmed death ligand 1 (PD-L1), a key component within tEVs, induced DNA damage and hyperactive lipid metabolism in both human and mouse T cells. This caused an elevated expression of lipid metabolic enzymes and an increase in cholesterol and lipid droplet formation, leading to cellular senescence. At a molecular level, PD-L1 derived from tEVs activated the cAMP-response element binding protein (CREB) and signal transducer and activator of transcription (STAT) signaling, which promoted lipid metabolism and facilitated senescence in human and mouse T cells. Inhibiting EV synthesis in tumors or blocking CREB signaling, cholesterol synthesis, and lipid droplet formation in effector T cells averted the tEV-mediated T cell senescence in vitro and in vivo in cell adoptive transfer and melanoma mouse models. The same treatments also bolstered the antitumor efficacy of adoptive transfer T cell therapy and anti-PD-L1 checkpoint immunotherapy in both human and mouse melanoma models. These studies identified mechanistic links between tumor-mediated immune suppression and potential immunotherapy resistance, and they provide new strategies for cancer immunotherapy.

DOI: https://doi.org/10.1126/scitranslmed.adm7269
Adv Exp Med Biol. 2025 ;1468 3-7

Associations of the Adaptive Immune System and Age-Related Macular Degeneration.

Lucas Stürzbecher, Olaf Strauss.

  In recent years, the adaptive immune system has gained a significant amount of attention due to its potential role in age-related macular degeneration (AMD). Orthologous approaches including cellular and animal models as well as pilot clinical trials have paved the way to understand the occurrence, alterations, and interactions of T cell populations in the retina. Interestingly, the notions of the involvement of the adaptive immune system in AMD have also gained support through recent findings in various neurodegenerative and chronic low-grade diseases, including multiple sclerosis, Parkinson's disease, or arteriosclerosis. In this group of pathologies, cells of the adaptive immune system bypass immune barriers and fuel inflammatory processes at immune-privileged sites. These findings have pointed at immunosenescence as a critical pro-inflammatory process involving T cell biology. Using a murine model relevant to the pathophysiology of geographic atrophy, we have demonstrated that specific populations of memory T cells are recruited to the retina prior to neurodegeneration. The investigation of these retinas at later degenerative stages revealed the presence of activated cytotoxic T cells at the injury site. These compelling results support the participation of the adaptive immune system in retina degeneration and highlight the potential of T cell populations as an early therapeutic target to slow the progression of AMD.

Keywords:  Adaptive immune system; Age-related macular degeneration; Geographic atrophy; Memory T cells; Neovascular AMD; Neurodegeneration; Pathophysiology; Retina; Senescence; T cells

DOI:  https://doi.org/10.1007/978-3-031-76550-6_1
Sci Immunol. 2025 Feb 14. 10(104): eadr0517

TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus.

Peng Shao, Regina M Antonetti, Tina Arkee, Emma L Hornick, Hai Hui Xue, Gail A Bishop, Noah S Butler.

CD4+ T follicular helper (TFH) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate TFH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for TFH cell differentiation and function during systemic inflammatory infections. Loss of CD4+ T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for TFH cell initiation and instead augmented TH1 development and function. TRAF3-deficient CD4+ T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue TFH cell differentiation. Human CD4+ T cells lacking TRAF3 exhibited impaired TFH polarization, supporting a conserved mechanism by which TRAF3 regulates CD4+ T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the TFH cell specification during infection.

DOI: https://doi.org/10.1126/sciimmunol.adr0517
J Immunother Cancer. 2025 Feb 11. pii: e009994. [Epub ahead of print]13(2):

CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors.

Asmaa O Mohamed, David Tyler Boone, Shannon L Ferry, Melanie C Peck, Alicia M Santos, Haille E Soderholm, Megen C Wittling, Chrystal Paulos, Mary Jo Turk, Yina H Huang.

   BACKGROUND: Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple strategies improve persistence by increasing stem-like properties or sustaining CAR T cell activity with combination therapies. Here, we describe the intrinsic ability of CAR T cells to differentiate into memory T cells, the effect of cytokine armoring, and neoadjuvant CD4 depletion therapy on CAR and tumor-specific endogenous memory T cells.
METHODS: TRP1-specific or NKG2D CAR T cells alone or with Super2+IL-33 (S233) armoring and/or CD4 depletion were evaluated in immunocompetent B16F10 melanoma or MC38 colon cell carcinoma models without preconditioning. We characterized CAR and endogenous tumor-specific memory T cell precursors, establishment of circulating (TCIRC) and resident (TRM) memory T cell subsets, and ability to protect against secondary tumors.
RESULTS: TRP1-specific or NKG2D CAR T cells had no effect on primary tumor growth in immunocompetent mice unless they were combined with S233 armoring or CD4 depletion. Unarmored CAR T cells expressed a stem-like phenotype in the tumor-draining lymph node and differentiated into CAR TCIRC memory cells in lymphoid organs and CAR TRM cells in the skin. In contrast, S233-armored CAR T cells exhibited an activated effector phenotype and differentiated inefficiently into CAR effector and central memory T cells. Combining CD4 therapy with unarmored CAR T cells increased CAR TCIRC and TRM memory T cells. Either CD4 depletion therapy or S233-armored CAR T cells induced activation of tumor-specific endogenous T cells that differentiated into both TCIRC and TRM memory T cells. CD4 depletion and S233-armored CAR T cell combination therapy synergized to increase endogenous memory T cells.
CONCLUSIONS: Unarmored TRP-1-specific or NKG2D CAR T cells have intrinsic stem-like properties and differentiate into memory T cell subsets but are non-protective against primary or secondary tumors. S233 cytokine armoring alone or with CD4 depletion improved effector responses but limited CAR memory T cell generation. S233-armored CAR T cells or CD4 depletion therapy induced endogenous tumor-specific TCIRC and TRM T cells, but the combination potentiated endogenous memory T cell generation and resulted in improved protection against B16F10 rechallenge.

Keywords:  Chimeric antigen receptor - CAR; Combination therapy; Melanoma; Memory; T cell

DOI:  https://doi.org/10.1136/jitc-2024-009994
Metabolism. 2025 Feb 11. pii: S0026-0495(25)00027-7. [Epub ahead of print]166 156158

Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction.

Fadi Khalaf, Dalia Barayan, Sean Saldanha, Marc G Jeschke.

  With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.

Keywords:  Adipose tissue; Aging; Burn injury; Hypermetabolism; Inflammaging; Metabolaging; Metabolism

DOI:  https://doi.org/10.1016/j.metabol.2025.156158
Semin Cancer Biol. 2025 Feb 09. pii: S1044-579X(25)00018-5. [Epub ahead of print]

Metabolic landscape and rewiring in normal hematopoiesis, leukemia and aging.

Hui Fang, Enze Yu, Chang Liu, Christy Eapen, Chunming Cheng, Tianxiang Hu.

  Recent advancements in metabolism research have demonstrated its critical roles in a lot of critical biological processes, including stemness maintenance, cell differentiation, proliferation, and function. Hematopoiesis is the fundamental cell differentiation process with the production of millions of red blood cells per second in carrying oxygen and white blood cells in fighting infection and cancers. The differentiation processes of hematopoietic stem and progenitor cells (HSPCs) are accompanied by significant metabolic reprogramming. In hematological malignancy, metabolic reprogramming is also essential to the malignant hematopoiesis processes. The metabolic rewiring is driven by distinct molecular mechanisms that meet the specific demands of different target cells. Leukemic cells, for instance, adopt unique metabolic profiles to support their heightened energy needs for survival and proliferation. Moreover, aging HSPCs exhibit altered energy consumption compared to their younger counterparts, often triggering protective mechanisms at the cellular level. In this review, we provide a comprehensive analysis of the metabolic processes involved in hematopoiesis and the metabolic rewiring that occurs under adverse conditions. In addition, we highlight current research directions and discuss the potential of targeting metabolic pathways for the management of hematological malignancies and aging.

Keywords:  aging; hematopoiesis; hematopoietic stem and progenitor cells; malignant hematopoiesis; metabolic rewiring; metabolism

DOI:  https://doi.org/10.1016/j.semcancer.2025.02.003
Adv Exp Med Biol. 2025 ;1468 165-169

Potential Role of NUR77 in the Aging Retinal Pigment Epithelium and Age-Related Macular Degeneration.

Tanu Parmar, Vipul Parmar, Goldis Malek.

  The underlying mechanisms associated with age-related changes in the morphology and function of retinal pigmented epithelial (RPE) cells are poorly understood. The aging RPE progresses through several structural changes including loss of melanin granules, accumulation of lipofuscin, and cytoskeletal changes, among others. Extracellular to it, there is also thickening of Bruch's membrane and changes in the integrity of the choroid. Recent studies have revealed that aging also affects the metabolic ecosystem of the RPE. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species generation, and increased number of mitochondrial mutations relative to baseline. These changes are also found in age-related macular degeneration (AMD), a late-onset vision-impairing disease, in which the RPE is particularly vulnerable. The orphan nuclear receptor NR4A1/NUR77 is an early response gene and regulator of various cellular processes during development, aging, and disease. Previously we observed decreased levels of Nur77/NUR77 in both mouse and human RPE as a function of age. Current knowledge of the function of this receptor in the RPE is limited. Herein, we discuss the putative roles of NUR77 in the RPE during aging and disease.

Keywords:  Age-related macular degeneration; Aging; Cell metabolism; Nur77; Retinal pigment epithelial cells

DOI:  https://doi.org/10.1007/978-3-031-76550-6_27
Cell Death Dis. 2025 Feb 12. 16(1): 90

TIGIT expression in extrahepatic cholangiocarcinoma and its impact on CD8 + T cell exhaustion: implications for immunotherapy.

Tengqian Tang, Wenhao Wang, Lang Gan, Jie Bai, Dehong Tan, Yan Jiang, Ping Zheng, Weijun Zhang, Yu He, Qianfei Zuo, Leida Zhang.

Extrahepatic cholangiocarcinoma (ECCA) is a malignant tumor. The precise role of T-cell immunoreceptor with Ig and ITIM domains (TIGIT), an emerging immunosuppressive receptor, in ECCA, and its impact on CD8+ T cell exhaustion (Tex) remains unclear. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating lymphocytes (TILs) isolated from ECCA. We found that TIGIT was significantly overexpressed in TOX+CD8 T cells. Tissue microarray and immunohistochemistry staining demonstrated that increased TIGIT expression was associated with poorer patient survival. Flow cytometry analysis revealed that TIGIT+CD8+ T cells exhibited decreased TNF-α, IFN-γ, and TCF-1 expression, accompanied by elevated PD-1 and TIM-3 expression compared to TIGIT-CD8+ T cells. In the patient-derived xenograft (PDX) model, the anti-TIGIT treatment group demonstrated reduced tumor weight, enhanced CD8 frequency, and an increased IFN-γ proportion compared to the PBS treatment group. The TIGIT antibody-treated group exhibited a notably higher fraction of GRZB, and anti-TIGIT treatment led to elevated TCF-1 protein levels and decreased protein levels of TOX1 and NR4A1. Moreover, TIGIT+CD8 T cells from TILs appear to be in a state of exhaustion with low potential killing capacity in ECCA, as shown by scRNA-seq. Taken together, the present study underscores the significant role of TIGIT in ECCA, contributing to T cell exhaustion and a compromised CD8+ T cell immune response. Targeting TIGIT presents a promising therapeutic avenue to enhance the CD8+ T-cell response, thereby potentially improving ECCA therapeutic benefits.

DOI: https://doi.org/10.1038/s41419-025-07388-4
J Clin Invest. 2025 Feb 11. pii: e185489. [Epub ahead of print]

Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo.

Wenli Mu, Shallu Tomer, Jeffrey Harding, Nandita Kedia, Valerie Rezek, Ethan Cook, Vaibhavi Patankar, Mayra A Carrillo, Heather Martin, Hwee L Ng, Li Wang, Matthew D Marsden, Scott D Kitchen, Anjie Zhen.

  Chimeric Antigen Receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and non-human primates (NHPs) demonstrate that hematopoietic stem cell (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional anti-viral CAR-T cells that reduce viral rebound after ART withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle for sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondria respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells and improved CAR-T control of viral replication. RNAseq analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and the upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound post-ART and reduced HIV reservoir compared to CAR-HSCs alone. These findings suggest that HSCs-based anti-HIV CAR-T combined with rapamycin treatment is a promising approach for treating persistent inflammation and improving immune control of HIV replication.

Keywords:  AIDS/HIV; Immunology; Immunotherapy; T cells

DOI:  https://doi.org/10.1172/JCI185489
Signal Transduct Target Ther. 2025 Feb 14. 10(1): 53

Restoring the supply lines: removing roadblocks to fatty acid uptake enhances T cell-driven cancer fight.

Jeremy G Baldwin, Caio R F Silveira, Luca Gattinoni.

DOI: https://doi.org/10.1038/s41392-025-02151-9
Blood Adv. 2025 Feb 12. pii: bloodadvances.2024014822. [Epub ahead of print]

Mitigating T-Cell Mitochondrial Dysfunction in CLL to Augment CAR T-Cell Therapy: Evaluation in an Immunocompetent Model.

Wael Gamal, Nienke B Goedhart, Helga Simon-Molas, Melanie Mediavilla-Varela, Angimar Uriepero-Palma, Fleur S Peters, Kamira Maharaj, Julio C Chavez, John J Powers, Alyssa Obermayer, Timothy I Shaw, José R Conejo-Garcia, Paulo C Rodriguez, Eva Sahakian, Javier Pinilla-Ibarz, Arnon P Kater.

An unmet clinical need in chronic lymphocytic leukemia (CLL) is emerging due to the rapidly expanding group of patients with double refractory (BTK- and Bcl2-inhibitor) disease. So far, autologous T-cell-based therapies, including chimeric antigen receptor (CAR) T-cells, have limited success in CLL, which has been attributed to an acquired CLL-mediated T-cell dysfunction and subset-skewing towards effector cells at the expense of memory formation. T-cell responses rely on dynamic metabolic processes, particularly mitochondrial fitness. While mitochondrial disruptions have been observed in solid tumor-infiltrating lymphocytes, their impact on T-cell immunity in lymphoproliferative disorders is unknown. Recent findings indicate that mitochondrial mass in CAR T-cells correlates with CLL clinical outcomes. This prompted an investigation into the mitochondrial fitness in CLL T-cells. Integrated metabolic and functional analyses revealed impaired, depolarized mitochondria across all T-cell subsets in untreated CLL patients, leading to further ex vivo and in vivo mouse studies on the underlying signaling alterations. Multi-omics profiling of transcriptome and epigenome revealed significant alterations in mitochondrial signaling, diminished AMP-activated protein kinase (AMPK) and autophagy activity, and upregulated glycolysis coupled with hyperactivation in the Akt kinase. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway during CLL T-cell culture induced metabolic reprogramming, enhancing mitochondrial activity, PPAR-gamma coactivator1α (PGC1α) expression, and memory differentiation. Underscoring clinical relevance, supplementation with the PI3kδ inhibitor idelalisib during CAR T-cell manufacturing improved persistence and long-term leukemia-free remissions in an immunocompetent murine model. Our study suggests that modulating the abnormal CLL T-cell metabolism can enhance the efficacy of autologous T-cell therapies.

DOI: https://doi.org/10.1182/bloodadvances.2024014822
Int Immunol. 2025 Feb 08. pii: dxaf006. [Epub ahead of print]

The TET-TDG axis in T cells and biological processes.

Kazumasa Suzuki, Anjana Rao, Atsushi Onodera.

  Ten-eleven translocation (TET) proteins are dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. In the "passive" (replication-dependent) DNA demethylation pathway, sequential oxidation reactions by TETs are essential and modified cytosines (C) are diluted at each cycle of DNA replication. In the "active" (replication-independent) DNA demethylation pathway, both thymine DNA glycosylase (TDG) and TETs play important roles. TDG removes 5fC and 5caC from 5fC:G and 5caC:G base pairs and these modified bases are replaced by unmodified C via base excision repair. Through epigenetic regulation of DNA demethylation, TETs and TDG are involved in cell development, differentiation, and homeostasis. The interplay between TDG and TETs is involved in embryo development, stem cell differentiation, neural development, immune responses, and tumorigenesis. Loss-of-function mutations of TET proteins in immune cells are associated with a variety of abnormalities, including inflammation, cancer, and clonal hematopoiesis, a condition related to aging. Loss of TETs also has a significant impact on the plasticity and differentiation of T cells, which contributes to inflammation and cancer. In this review, we describe recent findings in function of TETs in T cell plasticity and differentiation and the TET-TDG axis in selected biological processes.

Keywords:  DNA cytosine methylation; DNA demethylation; Ten-Eleven Translocation (TET); methylcytosine dioxygenases; thymine DNA glycosylase (TDG)

DOI:  https://doi.org/10.1093/intimm/dxaf006
ACS Omega. 2025 Feb 04. 10(4): 3610-3621

Dietary Natural Melanin Nanozymes Delay Aging and Ameliorate Neurodegeneration via Improving Gut Microbiota and Redox Homeostasis.

Yao Xiao, Shikun Zhang, Hailong Zhuo, Xiaoyong Zhang, Kai Zhu, Wanyi Chen, Guoxing You, Hongwei Chen, Qun Luo, Hong Zhou, Gan Chen.

Aging is an inevitable multifactor process that causes a decline in organ function and increases the risk of age-related diseases and death. Thus, the development of highly effective and safe therapeutic strategies to delay aging and age-related diseases is urgently required. In this study, we isolated natural melanin nanozymes (NMNs) from the ink sacs of live octopuses. The NMNs exhibited excellent superoxide-dismutase-mimicking and radical scavenging activities. In SAMP8 mice, treatment with NMNs improved their cognition and memory functions while restoring their aging-impaired liver function and lipid metabolism, thereby prolonging their lifespan. Moreover, the NMNs reversed metabolic changes in their aged brains and reconstructed their gut microbiota composition by enhancing microbial community diversity. Our findings indicate that NMNs treatment could be a promising approach for delaying aging and preventing age-associated physiological decline in humans.

DOI: https://doi.org/10.1021/acsomega.4c08419