bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–05–11
twenty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
  2. T Cell Aging: An Important Target for Perioperative Immunomodulation.
  3. Progenitor exhausted T cells contribute to the formation of immunological memory.
  4. CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis.
  5. [The Latest Research Progress of T Cell Exhaustion in Hematological Malignancy --Review].
  6. BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.
  7. The MYC/TXNIP axis mediates NCL-Suppressed CD8+T cell immune response in lung adenocarcinoma.
  8. Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming.
  9. Hdac1 as an early determinant of intermediate-exhausted CD8+ T cell fate in chronic viral infection.
  10. Harnessing nutrient scarcity for enhanced CAR-T-cell potency and safety in solid tumors.
  11. Quadruple adenine base-edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease-engineered T cells.
  12. A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury: current capabilities and challenges for future predictivity.
  13. SPP1 + macrophages cause exhaustion of tumor-specific T cells in liver metastases.
  14. HDLBP Promotes Glycolysis and CD8+ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.
  15. Immunosuppressive Effects of Multiple Myeloma-Derived Extracellular Vesicles Through T Cell Exhaustion.
  16. Scavenging Reactive Oxygen Species by Cerium Oxide Nanoparticles Prevents Death in a Peripheral T Cell Lymphoma Preclinical Mouse Model.
  17. EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8+ T cells toward less-exhausted phenotypes.
  18. From ex vivo to in vitro models: towards a novel approach to investigate the efficacy of immunotherapies on exhausted Vγ9Vδ2 T cells?
  19. NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity.
  20. Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
  21. Increased CD8dim and Decreased CD8bright T Cells as Immunological Signature for Multibacilary Leprosy Patients.
  1. Nat Commun. 2025 May 08. 16(1): 4292
    Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
    Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger.
      T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.
    DOI:  https://doi.org/10.1038/s41467-025-59310-3
  2. Clin Interv Aging. 2025 ;20 537-557
    T Cell Aging: An Important Target for Perioperative Immunomodulation.
    Haoning Lan, Songchao Xu, Huili Li, Ruijuan Guo, Zhong Feng, Yun Wang.
      Although T cells are crucially involved in maintaining immune function, their roles change with age. Furthermore, T cell aging has a unique onset and progression mechanism and several clinical indicators have been developed to detect it. Moreover, perioperative pain and stressful stimuli could affect the body's immune status, influencing patients' recovery. This article examines how preoperative and intraoperative complications influence T cell aging. These factors include conditions such as hypertension, diabetes, acute respiratory distress syndrome, hypoxemia, depression, pain, obesity, neurologic diseases, tumors, autoimmune diseases, as well as aspects like anesthetic modalities, types of surgery, and medications. This analysis could help identify groups at a high risk of perioperative T cell aging. For example, elderly cancer patients with multiple chronic diseases may be the most affected by T cell aging. We also discuss the effects of T cell aging on postoperative phenomena such as neurological dysfunction and recovery quality. Based on insights from this discussion, we deduced that prehabilitation, pharmacological treatment, and adoptive neuro-immunotherapy could modulate T cell aging in the perioperative period, thus improving clinical prognosis.
    Keywords:  CD57; T cell aging; immunomodulation; perioperative period; senescence-associated secretory phenotype; terminal effector memory T cells
    DOI:  https://doi.org/10.2147/CIA.S519438
  3. Nat Rev Immunol. 2025 May 06.
    Progenitor exhausted T cells contribute to the formation of immunological memory.
    Annette Wu, Wen Jiang.
      
    DOI:  https://doi.org/10.1038/s41577-025-01182-1
  4. J Immunol. 2025 May 05. pii: vkaf075. [Epub ahead of print]
    CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis.
    Thi Tran Ngoc Minh, Lotte J Verleng, Ellen Schrama, Julia Busselaar, Mo D Staal, Evert de Vries, Jacqueline D H Anholts, Celia R Berkers, Jannie Borst, Esther A Zaal, Sander de Kivit.
      T cells undergo many metabolic changes throughout the different phases of their response in lymphoid and nonlymphoid tissues. Cell metabolism meets demands for energy and biosynthesis, particularly during cell division and effector differentiation. As costimulatory receptors, CD28 and various TNF receptor (TNFR) family members shape T-cell clonal expansion, survival and effector functions and are important clinical targets. While CD28 is acknowledged as a metabolic regulator, little is known about how TNFRs shape T-cell metabolism. We here identify TNFR family member CD27 as a metabolic regulator in activated human CD4+ T cells. In the context of CD3 signaling and CD28 costimulation, CD27 proved to regulate specific metabolic functions, as determined by metabolomics and metabolic tracer experiments. CD27 costimulation supported upregulation of glycolysis, the pentose phosphate pathway and the TCA cycle, increasing the use of glucose-derived carbon and glutamine-derived nitrogen as building blocks for de novo nucleotide synthesis. It also promoted uptake of amino acids (AAs) and modulated pathways of AA metabolism. Accordingly, CD27 costimulation boosted protein translation in CD3- and CD3/CD28-activated CD4+ T cells, which proceeded via enhanced mTOR pathway activation. Remarkably, CD27, OX40 and 4-1BB all enhanced CD3-induced mTOR signaling, but only CD27 could overrule inhibitory PD-1 signaling. CD27 costimulation increased IL-2, IFNγ and TNFα production by CD3-activated CD4+ T cells, also in presence of PD-1 signaling. Next to previously defined beneficial effects of CD27 on activated T-cell survival and CTL differentiation and Th1 effector differentiation, these data support its essential contribution to T-cell metabolism and its relevance as a therapeutic target.
    Keywords:  CD27; T cell; TNFR; costimulation; metabolism
    DOI:  https://doi.org/10.1093/jimmun/vkaf075
  5. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Apr;33(2): 606-611
    [The Latest Research Progress of T Cell Exhaustion in Hematological Malignancy --Review].
    Xia-Xin Liu, Zi-Zhen Xu, Jun-Min Li.
      T cell exhaustion plays an immunosuppressive role in malignant tumors. Continuous tumor antigen stimulation, the presence of suppressive immune cells and cytokines in the tumor microenvironment, the up regulation of inhibitory receptor expression on the surface of T cells, changes in T cell related transcription factors, and metabolites in the tumor microenvironment may lead to T cell exhaustion. Reversing the exhaustion of T cells in tumor patients is a promising strategy for tumor immunotherapy. This article will review the latest research progress on T cell exhaustion status, pathogenesis, reversal methods, and clinical applications in hematological tumors.
    Keywords:   T cell exhaustion; hematological tumor; immunotherapy
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.02.045
  6. J Exp Med. 2025 Aug 04. pii: e20241133. [Epub ahead of print]222(8):
    BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.
    Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng.
      In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor-exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of ∼216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
    DOI:  https://doi.org/10.1084/jem.20241133
  7. Mol Med. 2025 May 09. 31(1): 180
    The MYC/TXNIP axis mediates NCL-Suppressed CD8+T cell immune response in lung adenocarcinoma.
    Dan Xiao, Tanxiu Chen, Xinlin Yu, Ying Song, Yigang Liu, Wei Yan.
       BACKGROUND: Lung adenocarcinoma is a deadly malignancy with immune evasion playing a key role in tumor progression. Glucose metabolism is crucial for T cell function, and the nucleolar protein NCL may influence T cell glucose metabolism. This study aims to investigate NCL's role in T cell glucose metabolism and immune evasion by lung adenocarcinoma cells.
    METHODS: Utilizing single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed cell clustering, annotation, and prognosis. In vitro experiments involved manipulating NCL expression in CD8+ T cells to study immune function and glucose metabolism. In vivo studies using an orthotopic transplant mouse model monitored NCL's impact on CD8+ T cell glucose metabolism and anti-tumor immune function.
    RESULTS: NCL was associated with T cell dysfunction and glucose metabolism. NCL silencing enhanced CD8+ T cell glucose metabolism, cytotoxicity, and infiltration, while NCL overexpression had the opposite effect. NCL overexpression relieved MYC-mediated transcriptional repression of TXNIP, reducing CD8+ T cell glucose metabolism. In vivo, NCL inhibited CD8+ T cell glucose metabolism through the MYC/TXNIP axis, hindering anti-tumor immune function.
    CONCLUSIONS: NCL overexpression suppresses CD8+ T cell glucose metabolism and anti-tumor immune function, promoting lung adenocarcinoma progression via the MYC/TXNIP axis.
    Keywords:  CD8+ T cells; Glucose metabolism; Immune escape; Lung adenocarcinoma; MYC; NCL
    DOI:  https://doi.org/10.1186/s10020-025-01224-3
  8. Cell Metab. 2025 Apr 30. pii: S1550-4131(25)00218-9. [Epub ahead of print]
    Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming.
    Congyi Niu, Huan Wei, Xuanxuan Pan, Yuedi Wang, Huan Song, Congwen Li, Jingbo Qie, Jiawen Qian, Shaocong Mo, Wanwei Zheng, Kameina Zhuma, Zixin Lv, Yiyuan Gao, Dan Zhang, Hui Yang, Ronghua Liu, Luman Wang, Wenwei Tu, Jie Liu, Yiwei Chu, Feifei Luo.
      The tumor microenvironment, characterized by low oxygen tension and scarce nutrients, impairs chimeric antigen receptor (CAR)-T cell metabolism, leading to T cell exhaustion and dysfunction. Notably, Foxp3 confers a metabolic advantage to regulatory T cells under such restrictive conditions. Exploiting this property, we generated CAR-TFoxp3 cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-TFoxp3 cells exhibited distinct metabolic reprogramming, marked by downregulated aerobic glycolysis and oxidative phosphorylation coupled with upregulated lipid metabolism. This metabolic shift was driven by Foxp3's interaction with dynamin-related protein 1. Crucially, CAR-TFoxp3 cells did not acquire regulatory T cell immunosuppressive functions but instead demonstrated enhanced antitumor potency and reduced expression of exhaustion markers via Foxp3-mediated adaptation. The potent antitumor effect and absence of immunosuppression were confirmed in a humanized immune system mouse model. Our findings establish a metabolic reprogramming-based strategy to enhance CAR-T cell adaptability within the hostile tumor microenvironment while preserving therapeutic efficacy.
    Keywords:  CAR-T cell; Drp1; Foxp3; exhaustion; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.008
  9. Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2502256122
    Hdac1 as an early determinant of intermediate-exhausted CD8+ T cell fate in chronic viral infection.
    Wei Hu, Shengen Shawn Hu, Shaoqi Zhu, Weiqun Peng, Vladimir P Badovinac, Chongzhi Zang, Xudong Zhao, Hai-Hui Xue.
      The exhausted CD8+ T (TEX) cells consist of distinct subsets including Tcf1+ stem-like, Tcf1-Cx3cr1+ intermediate (TEX-int) and Tcf1-Cx3cr1- terminally exhausted cells; yet, epigenetic determinants of TEX subset differentiation remain incompletely understood. Using chronic viral infection, we show that histone deacetylase 1 (Hdac1) was specifically required for the formation of antigen-specific TEX-int cells at the effector phase of responses. Single-cell transcriptomics validated that Hdac1 deficiency depleted TEX-int cells and revealed that Hdac1 was critical for positive regulation of TEX-int-characteristic genes, including Cx3cr1, Cxcr6, and Klf2. Furthermore, profiling chromatin accessibility landscape in TEX subsets demonstrated that loss of Hdac1 resulted in a prevalent increase in chromatin open state, as evidently observed at the exhaustion program genes, which were linked to induced expression of exhaustion-inducing Tox transcription factor, PD1 and Lag3 coinhibitory receptors in TEX cells. Hdac1 thus has dual regulatory functions: promoting TEX-int cell fate and preventing excessive activation of the exhaustion program to curtail uncontrolled virus replication.
    Keywords:  T cell exhaustion; epigentic regulation; histone deacetylase; transitory state
    DOI:  https://doi.org/10.1073/pnas.2502256122
  10. Cell Mol Immunol. 2025 May 08.
    Harnessing nutrient scarcity for enhanced CAR-T-cell potency and safety in solid tumors.
    Enzo Manchon, Nell Hirt, Benjamin Versier, Aravindhan Soundiramourty, Ludmila Juricek, Celeste Lebbe, Maxime Battistella, Yves Christen, Jacques Mallet, Dominique Charron, Nabila Jabrane-Ferrat, Che Serguera, Reem Al-Daccak.
      Despite significant advancements, the effectiveness of chimeric antigen receptor (CAR)-T-cell-based therapies in solid tumors remains limited. Key challenges include on-target effects, off-tumor toxicity and reduced CAR-T-cell function within the tumor microenvironment, which is often characterized by metabolic stress triggered by factors such as amino acid scarcity. Activating transcription factor-4 (ATF4) and its upstream regulator GCN2 play crucial roles in the metabolic reprogramming and functionality of CD4+ and CD8+ T cells. ATF4 can be activated by various cellular stress signals, including amino acid deprivation. While ATF4 activation may be associated with T-cell dysfunction, its role in stress adaptation presents an opportunity for therapeutic intervention-particularly in the tumor microenvironment, where T-cell exhaustion is a major challenge. In this study, we developed a strategy to harness the GCN2‒ATF4 axis in CAR-T cells. We employed an amino acid-dependent inducible promoter, which triggers ATF4-dependent gene expression to regulate CAR expression in T cells under conditions of amino acid scarcity within the tumor microenvironment. In vitro and murine xenograft models demonstrate the potential of this system to effectively restrict CAR expression to the tumor site. This targeted strategy not only enhances safety by minimizing off-tumor activity but also CAR-T-cell fitness by reducing exhaustion. By validating this pathophysiologically regulatable CAR expression system for solid tumors, our findings address key limitations of current CAR-T-cell therapies and pave the way for innovative strategies targeting solid malignancies.
    Keywords:  Amino acid scarcity; CAR-T; Solid tumours; Tumour microenvironment
    DOI:  https://doi.org/10.1038/s41423-025-01290-x
  11. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2427216122
    Quadruple adenine base-edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease-engineered T cells.
    Nils W Engel, Israel Steinfeld, Daniel Ryan, Kusala Anupindi, Samuel Kim, Nils Wellhausen, Linhui Chen, Katherine Wilkins, Daniel J Baker, Philipp C Rommel, Danuta Jarocha, Mercy Gohil, Qian Zhang, Michael C Milone, Joseph A Fraietta, Megan Davis, Regina M Young, Carl H June.
      Genome-editing technologies have enabled the clinical development of allogeneic cellular therapies, yet the optimal gene-editing modality for multiplex editing of therapeutic T cell product manufacturing remains elusive. In this study, we conducted a comprehensive comparison of CRISPR/Cas9 nuclease and adenine base editor (ABE) technologies in generating allogeneic chimeric antigen receptor (CAR) T cells, utilizing extensive in vitro and in vivo analyses. Both methods achieved high editing efficiencies across four target genes, critical for mitigating graft-versus-host disease and allograft rejection: TRAC or CD3E, B2M, CIITA, and PVR. Notably, ABE demonstrated higher manufacturing yields and distinct off-target profiles compared to Cas9, with translocations observed exclusively in Cas9-edited products. Functionally, ABE-edited CAR T cells exhibited superior in vitro effector functions under continuous antigen stimulation, including enhanced proliferative capacity and increased surface CAR expression. Transcriptomic analysis revealed that ABE editing resulted in reduced activation of p53 and DNA damage response pathways at baseline, along with sustained activation of metabolic pathways during antigen stress. Consistently, Assay for Transposase-Accessible Chromatin using sequencing data indicated that Cas9-edited, but not ABE-edited, CAR T cells showed enrichment of chromatin accessibility peaks associated with double-strand break repair and DNA damage response pathways. In a preclinical leukemia model, ABE-edited CAR T cells demonstrated improved tumor control and extended overall survival compared to their Cas9-edited counterparts. Collectively, these findings position ABE as superior to Cas9 nucleases for multiplex gene editing of therapeutic T cells.
    Keywords:  CRISPR/Cas9; adenine base editor; chimeric antigen receptor
    DOI:  https://doi.org/10.1073/pnas.2427216122
  12. Expert Opin Drug Metab Toxicol. 2025 May 06. 1-11
    A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury: current capabilities and challenges for future predictivity.
    Lara Clemens, Christina Battista, Zackary R Kenz, Lisl K M Shoda.
       BACKGROUND: Drug-induced liver injury (DILI) is an adverse event whose emergence can slow or halt drug development programs. Adaptive immune responses have been implicated for several DILI compounds, and drug-specific T cell responses have been characterized, but there are still many unknowns. We describe the extension of a quantitative systems toxicology (QST) model of DILI to include CD8+ T cell-mediated DILI.
    RESEARCH DESIGN AND METHODS: To overcome deficits in quantitative data characterizing CD8+ T cell-mediated DILI, a translational strategy leveraged a well-defined mouse ovalbumin (OVA) antigen model and adapted it to represent mouse amodiaquine (AQ)-specific CD8+ T cell-mediated DILI, with further adaptations to represent human AQ-specific CD8+ T cell-mediated DILI.
    RESULTS: DILIsym reproduced published data characterizing mouse OVA-specific CD8+ T cell-mediated hepatotoxicity, mouse AQ-specific CD8+ T cell-mediated DILI, and human AQ-specific CD8+ T cell-mediated DILI. Development identified main drivers of the CD8+ T cell response, as well as areas where in vitro assay data could inform the simulation of additional compounds.
    CONCLUSIONS: The DILIsym CD8+ T cell sub-model is well-positioned for systematic testing to improve our understanding of CD8+ T cell-mediated DILI. It is not yet predictive but indicates a promising direction to reduce DILI events in drug development.
    Keywords:  Alanine aminotransferase (ALT); CD8+ T cells; DILIsym; drug-induced liver injury (DILI); quantitative systems toxicology (QST)
    DOI:  https://doi.org/10.1080/17425255.2025.2499551
  13. Nat Commun. 2025 May 07. 16(1): 4242
    SPP1 + macrophages cause exhaustion of tumor-specific T cells in liver metastases.
    Rajiv Trehan, Patrick Huang, Xiao Bin Zhu, Xin Wang, Marlaine Soliman, Dillon Strepay, Amran Nur, Noemi Kedei, Martin Arhin, Shadin Ghabra, Francisco Rodríguez-Matos, Mohamed-Reda Benmebarek, Chi Ma, Firouzeh Korangy, Tim F Greten.
      Functional tumor-specific CD8+ T cells are essential for effective anti-tumor immune response and immune checkpoint inhibitor therapy. Here we show that, compared to other organ sites, primary, metastatic liver tumors in murine models contain a higher number of tumor-specific CD8+ T cells which are also dysfunctional. High-dimensional, multi-omic analysis of patient samples reveals a higher frequency of exhausted tumor-reactive CD8+ T cells and enriched interactions between these cells and SPP1+ macrophages in profibrotic, alpha-SMA rich regions specifically in the liver. Differential pseudotime trajectory inference analysis reveals that extrahepatic signaling promotes an intermediate cell (IC) population in the liver, characterized by co-expression of VISG4, CSF1R, CD163, TGF-βR, IL-6R, and SPP1. Analysis of premetastatic adenocarcinoma patient samples reveals enrichment of this population may predict liver metastasis. These findings suggest a mechanism by which extrahepatic tumors drive liver metastasis by promoting an IC population that inhibits tumor-reactive CD8+ T cell function.
    DOI:  https://doi.org/10.1038/s41467-025-59529-0
  14. Am J Respir Cell Mol Biol. 2025 May 09.
    HDLBP Promotes Glycolysis and CD8+ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.
    Li Xu, Bin Zhou, Kaiqi Jin, Tao Ge, Ming Deng, Hongdou Ding, Xinnan Xu.
      Gap junction protein beta 2 (GJB2) has been associated with glycolysis and immunosuppression in human tumors. This research aims to explore the roles of GJB2 in these aspects in the context of lung adenocarcinoma (LUAD). GJB2 expression in LUAD was analyzed using bioinformatics tools and verified in human LUAD cells. RNA binding proteins (RBPs) that target GJB2 were predicted using bioinformatics and verified using RNA immunoprecipitation assays. Gain- or loss-of-function assays of GJB2 and high-density lipoprotein binding protein (HDLBP) were performed in LUAD cells, investigating their roles in glycolysis. These LUAD cells underwent co-culture with activated CD8+ T cells to examine the effect of gene interference on the exhaustion and activity of T cells. A mouse model of allograft tumor was established for in vivo validation. GJB2 exhibited aberrantly heightened expression in LUAD cells. Further overexpression of GJB2 in cancer cells increased glucose uptake, lactate production, and extracellular acidification rate, augmented aggressive phenotype of cancer cells, and increased exhaustion of the co-cultured CD8+ T cells. HDLBP, an RBP that binds to GJB2 RNA, was found to be highly expressed in LUAD as well, which enhanced GJB2 expression by stabilizing the GJB2 mRNA. Overexpression of HDLBP similarly rendered glycolysis and T cell inactivity, with these effects negated by GJB2 knockdown. Parallelly, GJB2 silencing in mouse 3LL cells suppressed tumorigenesis, glycolysis, and T cell exhaustion in mice promoted by HDLBP. This research suggests that HDLBP-mediated GJB2 RNA stabilization augments glycolysis and CD8+ T cell exhaustion in LUAD progression.
    Keywords:  GJB2; Glycolysis; HDLBP; Immunosuppression; RNA stability
    DOI:  https://doi.org/10.1165/rcmb.2024-0648OC
  15. Cancer Sci. 2025 May 08.
    Immunosuppressive Effects of Multiple Myeloma-Derived Extracellular Vesicles Through T Cell Exhaustion.
    Shinya Hagiwara, Masaki Ri, Toru Ebina, Yoshiaki Marumo, Tomoyuki Nakamura, Kentaro Hirade, Takahiro Nakashima, Arisa Asano, Shiori Kinoshita, Tomotaka Suzuki, Tomoko Narita, Ayako Masaki, Hirokazu Komatsu, Shinsuke Iida.
      Extracellular vehicles (EVs) are reported to be involved in several processes relating to tumor progression, including angiogenesis, osteolysis, and drug resistance in multiple myeloma (MM). However, the role of EVs in the immune-suppressive milieu of MM is poorly understood. Here, we investigated the effects of MM-derived EVs on T cells, focusing on markers of T cell exhaustion. Using activated peripheral blood mononuclear cells from healthy donors, we observed immunosuppressive effects such as upregulated expression of immune checkpoint markers on CD8+ T cells treated with MM-derived EVs. Proteomic analysis identified several proteins, such as IL-8, SLC1A5, PIN2, and FSP1, associated with regulation of T cell exhaustion and chronic inflammation. Surprisingly, sphingosine kinase 1 (SPHK1) was enriched in MM cell line-derived EVs, implicating SPHK1/S1P signaling in the immunosuppressive effect of MM EVs. Thus, MM-derived EVs may promote T cell exhaustion via upregulating the expression of immune checkpoint markers and thereby contribute to the formation of the immune-suppressive milieu of MM, resulting in impaired T cell activity.
    Keywords:  T‐cell exhaustion; extracellular vesicles; immune checkpoint proteins; multiple myeloma; sphingosine kinase 1
    DOI:  https://doi.org/10.1111/cas.70099
  16. ACS Nano. 2025 May 09.
    Scavenging Reactive Oxygen Species by Cerium Oxide Nanoparticles Prevents Death in a Peripheral T Cell Lymphoma Preclinical Mouse Model.
    Adrien Krug, Lena M Ernst, Rana Mhaidly, Joana Ramis, Muriel F Gusta, Neus G Bastus, Adriana Martinez-Turtos, Marie Tosolini, Léa Di Mascio, Gamze Tari, Laurent Boyer, Philippe Gaulard, François Lemonnier, Jean-Ehrland Ricci, Els Verhoeyen, Victor Puntes.
      Cancer cell survival and proliferation are correlated with increased metabolic activity and consequent oxidative stress, driving metabolic shifts that interfere with the immune response to malignant cells. This is the case of high-energy-demanding angioimmunoblastic T cell lymphoma (AITL), a highly aggressive cancer with poor survival rates, where malignant CD4+ PD-1high T cells show increased mitochondrial activity and Reactive oxygen species (ROS) accumulation. Here, we report that administration of ROS scavenging cerium oxide (CeO2) nanoparticles in an AITL preclinical mouse model leads to their preferential accumulation in the spleen, where the CD4+ PD-1high T cells driving malignancy were significantly reduced. This was accompanied by activation of previously exhausted cytotoxic CD8+ T cells, restoring their potent antitumor function. As a result, survival rates dramatically increase with no observed toxicity to healthy cells or tissues. Overall, it highlights the correlation between increased energy demand, increased mitochondrial mass, increased PD-1 expression, increased ROS production, and immune suppression and how this vicious loop can be stopped by scavenging ROS.
    Keywords:  AITL preclinical model; ROS; T cell lymphoma; antioxidant; cancer; cerium oxide nanoparticles; mitochondria
    DOI:  https://doi.org/10.1021/acsnano.5c02860
  17. Cell Rep. 2025 May 05. pii: S2211-1247(25)00423-1. [Epub ahead of print]44(5): 115652
    EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8+ T cells toward less-exhausted phenotypes.
    Andrea Gramatica, Itzayana G Miller, Adam R Ward, Farzana Khan, Tyler J Kemmer, Jared Weiler, Tan Thinh Huynh, Paul Zumbo, Andrew P Kurland, Louise Leyre, Yanqin Ren, Thais Klevorn, Dennis C Copertino, Uchenna Chukwukere, Callie Levinger, Thomas R Dilling, Noemi Linden, Nathan L Board, Emma Falling Iversen, Sandra Terry, Talia M Mota, Seden Bedir, Kiera L Clayton, Alberto Bosque, Lynsay MacLaren Ehui, Colin Kovacs, Doron Betel, Jeffry R Johnson, Mirko Paiardini, Ali Danesh, R Brad Jones.
      Persistent HIV reservoirs in CD4+ T cells pose a barrier to curing HIV infection. We identify overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4+ T cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the US Food and Drug Administration-approved drug tazemetostat increases surface expression of major histocompatibility complex (MHC) class I on CD4+ T cells, counterbalancing HIV Nef-mediated MHC class I downregulation. This improves CTL-mediated elimination of HIV-infected cells and suppresses viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevates MHC class I and the pro-apoptotic protein BIM in CD4+ T cells, facilitating CD8+ T cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promotes sustained skewing of CD8+ T cells toward less-differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a mechanism of CTL resistance and support the clinical evaluation of tazemetostat as a method of enhancing clearance of HIV reservoirs and improving CD8+ T cell function.
    Keywords:  CP: Immunology; CP: Microbiology; EZH2; HIV; HIV cure research; HIV reservoir; T cell exhaustion; T cell immunity; epigenetic regulation; tazemetostat
    DOI:  https://doi.org/10.1016/j.celrep.2025.115652
  18. Front Immunol. 2025 ;16 1556982
    From ex vivo to in vitro models: towards a novel approach to investigate the efficacy of immunotherapies on exhausted Vγ9Vδ2 T cells?
    Morgane Chauvet, Dorothée Bourges, Emmanuel Scotet.
      Human γδ T cells demonstrate remarkable and diverse antitumor properties driven by TCR-dependent activation. Their non-alloreactive nature and pivotal role in cancer immunity position them as attractive targets for immunotherapies. However, upon infiltrating tumors, due to mechanisms induced by the tumor microenvironment's immune evasion strategies, these cells frequently become exhausted, greatly weakening the efficacy and antitumor potential of novel immunotherapeutic treatments. While being extensively characterized in CD8+ T cells, research on γδ T cell exhaustion remains scarce. There is a growing need for comprehensive models to investigate the reinvigoration properties of exhausted γδ T cells. This review synthesizes current strategies and models for evaluating novel immunotherapies aimed at rejuvenating exhausted γδ T cells. It explores a progression of approaches, from ex vivo studies and in vivo murine models to emerging in vitro systems. The advantages and limitations of these models are discussed to provide a comprehensive understanding of their potential in advancing therapeutic research. Furthermore, recent findings suggesting in vitro exhaustion phenotypes closely mirror those observed ex vivo highlight opportunities for preclinical innovation. By refining these models, researchers can better optimize the immunotherapies targeting this unique T cell subset.
    Keywords:  T cell exhaustion; Vγ9Vδ2 T cell; cancer; immunotherapy; in vitro models
    DOI:  https://doi.org/10.3389/fimmu.2025.1556982
  19. J Physiol. 2025 May 05.
    NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity.
    Renata R Braga, Matheus B Rocha, Ana P Morelli, Raul G da Costa, Marcelo A S Mori, Adelino S R da Silva, José R Pauli, Dennys E Cintra, Eduardo R Ropelle.
      Brown adipose tissue (BAT) is a highly specialized thermogenic tissue and plays a critical role in controlling energy expenditure and metabolic homeostasis. BAT dysfunction is associated with body weight gain and metabolic disorders in mice models. Here, we investigated the influence of the NAD-biosynthesis pathway in the control of BAT metabolism and function. Using a wide multi-omics and phenotypic panel of isogenic strains of BXD mice, we found that the NAD-biosynthesis pathway in BAT is closely associated with body weight gain, adiposity, insulin resistance, oxygen consumption, exercise capacity and mitochondrial metabolism. Interestingly, the high-fat diet (HFD) treatment disrupted the NAD-biosynthesis pathway, reducing Nampt and NMNat3 protein contents and inducing severe mitochondrial dysfunction in BAT of mice. Finally, the oral treatment with nicotinamide riboside (NR), an NAD+ precursor, significantly boosted NAD+ levels and preserved the morphofunctional mitochondria aspects of mitochondria, and the thermogenesis capacity of BAT in HFD-fed mice. These data point to the NAD synthesis pathway as a promising therapeutic adjuvant target in body thermogenesis management. KEY POINTS: Obesity impairs the NAD+ biosynthesis pathway, leading to mitochondrial dysfunction and reduced thermogenic capacity. NAD+ metabolism enzymes Nampt and NMNat3 are crucial for mitochondrial function in BAT. Nicotinamide riboside treatment increases the expression of key thermogenic proteins and NAD+-related enzymes in BAT, optimizing adaptive thermogenesis and mitochondria function.
    Keywords:  BAT; NAD; mitochondria; obesity
    DOI:  https://doi.org/10.1113/JP288453
  20. Front Cell Dev Biol. 2025 ;13 1584987
    Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
    Jun Lin, Xian-Lu He, Wei-Wei Zhang, Chun-Fen Mo.
      Tumor-associated neutrophils (TANs), pivotal immune cells within the tumor microenvironment (TME), exhibit dual potential in both pro- and anti-tumorigenic effects. These cells display remarkable heterogeneity and plasticity within the TME, adapting to hypoxic and nutrient-deprived conditions through metabolic reprogramming while critically influencing tumor progression, metastasis, and immune evasion. The metabolic reprogramming of TANs not only modulates their functional phenotypes but also reshapes tumor biological behaviors and therapeutic responses by regulating metabolic intermediates and cellular interactions within the TME. Therefore, elucidating the mechanisms underlying TANs metabolic reprogramming has significant implications for deciphering the molecular basis of tumorigenesis, identifying novel therapeutic targets, and optimizing immunotherapeutic strategies. This review systematically summarizes current knowledge regarding metabolic reprogramming mechanisms of TANs in the TME and their impact on tumor progression. We particularly focus on: 1) TAN-specific alterations in glucose, lipid, and amino acid metabolism within the TME; 2) Emerging immunotherapeutic strategies targeting TANs metabolic pathways; 3) Recent advances in understanding TAN-mediated immune evasion and therapy resistance. Furthermore, this review discusses potential challenges and corresponding solutions in targeting TANs metabolic reprogramming for therapeutic intervention, aiming to provide novel insights for advancing cancer immunotherapy.
    Keywords:  immunotherapy; metabolic reprogramming; therapeutic resistance; tumor microenvironment; tumor-associated neutrophils
    DOI:  https://doi.org/10.3389/fcell.2025.1584987
  21. Immunology. 2025 May 05.
    Increased CD8dim and Decreased CD8bright T Cells as Immunological Signature for Multibacilary Leprosy Patients.
    Yuri Scheidegger de Castro, Letícia Silva Nascimento, Juliana Azevedo da Silva, Rebeka da Conceição Souza, Gabriel Nogueira Araújo, Sandra Chalhub de Oliveira, Edilbert Pellegrini Nahn Junior, Alba Lucínia Peixoto-Rangel.
      Leprosy, a chronic infectious disease caused by Mycobacterium leprae, manifests in a spectrum of clinical forms and severity. This study investigated the percentage of CD8+ T cells and their subpopulations (CD8bright and CD8dim T cells) in leprosy patients stratified by clinical forms, bacterial load, and age. No significant differences were observed in the overall percentage of CD8+ T cells among healthy controls and leprosy patients. However, an increased percentage of CD8dim T cells and a decreased percentage of CD8bright T cells were associated with severe multibacillary and lepromatous forms of leprosy, independent of bacillary load. Further, these cellular profiles correlated more strongly with disease severity than with age, in spite of elderly multibacillary patients exhibiting significant reductions in CD8bright T cells and increases in CD8dim T cells compared to young or middle-aged paucibacillary patients, but not compared to young and middle-aged multibacillary patients. These findings suggest that CD8bright and CD8dim T cell profiles are critical indicators of disease progression and severity in leprosy, highlighting their potential as biomarkers for clinical evaluation.
    Keywords:   Mycobacterium leprae ; CD8bright and CD8dim T cells; lymphocytes
    DOI:  https://doi.org/10.1111/imm.13937
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