bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–01–26
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mannose: A game-changer for T cell immunotherapy.
  2. Generation of human and murine exhausted CD8+ T cells in vitro.
  3. Prion protein modulation of virus-specific T cell differentiation and function during acute viral infection.
  4. Nicotinamide riboside supplementation ameliorates ovarian dysfunction in a PCOS mouse model.
  5. Enhancing the effectiveness of immunotherapy in rheumatoid arthritis by delaying immunosenescence triggered by fibroblast-like synoviocytes.
  6. Unfolded protein responses in T cell immunity.
  7. Glut3 overexpression improves environmental glucose uptake and antitumor efficacy of CAR-T cells in solid tumors.
  8. Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice.
  9. Innovative PBMC-derived humanized mouse model reveals CD8+ T cell-intrinsic regulation during antitumor immunity.
  10. Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells.
  11. Immune evasion through mitochondrial transfer in the tumour microenvironment.
  12. Age-associated alterations in immune and inflammatory responses in captive olive baboons (Papio anubis).
  13. Aging and Cancer-Inextricably Linked Across the Lifespan.
  14. Therapeutic T cells with synthetic gene circuits act locally.
  15. Ageing and inflammation limit the induction of SARS-CoV-2-specific CD8+ T cell responses in severe COVID-19.
  16. Cancer cells 'poison' the immune system with tainted mitochondria.
  17. Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.
  18. Immune Dysregulation in Obesity.
  19. Hallmarks of aging: middle-aging hypovascularity, tissue perfusion and nitric oxide perspective on healthspan.
  1. Cell Metab. 2025 Jan 15. pii: S1550-4131(24)00496-0. [Epub ahead of print]
    Mannose: A game-changer for T cell immunotherapy.
    Jingwei Ma, Shuai Tong, Jingxuan Xiao, Bo Huang.
      Metabolism influences the behavior of various immune cell types. In a recent Cancer Cell study, Qiu et al. revealed mannose metabolism as a prominent metabolic feature of tumor precursor exhausted T cells (Tpex) that is crucial for maintaining T cell stemness. Their work uncovers a novel metabolic mechanism that decouples T cell proliferation from differentiation, providing valuable insights into how metabolic modulation can be used to generate "better" T cells during the manufacturing process.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.014
  2. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00216-4. [Epub ahead of print]191 93-114
    Generation of human and murine exhausted CD8+ T cells in vitro.
    Rosa Ana Lacalle, Raquel Blanco, Rebeca García-Lucena, Santos Mañes.
      T cell exhaustion is a state of dysfunction that can occur due to persistent exposure to antigens, such as in the tumor microenvironment. The progressive loss of effector functions in exhausted T cells can lead to resistance to immune checkpoint inhibitors and adoptive cell immunotherapies. Improving our understanding of the exhaustion process is thus crucial for optimizing the clinical outcomes of immunotherapy. A significant hurdle in this area is obtaining an adequate quantity of exhausted T cells. One solution could be the in vitro production of exhausted T cells by mimicking exhaustion-induced conditions. We present a simple, repeatable, flow cytometry-assisted method for generating exhausted CD8+ T cells from both human and mouse sources. This flexible protocol works with various cell sources and activation methods. Our results confirm the production of dysfunctional CD8+ T cells, akin to those in mouse tumor models and patient tumor samples. This methodology could help identify genes involved in the exhaustion process and serve as a platform for finding agents capable of altering, reversing, or accelerating this dysfunctional state. By using both mouse and human models, we increase the adaptability of the method, making it a powerful instrument for assessing potential substances with immunotherapeutic utility.
    Keywords:  CD8 T cell; Cancer; Differentiation; Dysfunction; Exhaustion; Immunotherapy
    DOI:  https://doi.org/10.1016/bs.mcb.2024.10.007
  3. Immunohorizons. 2025 Jan 23. pii: vlae002. [Epub ahead of print]9(1):
    Prion protein modulation of virus-specific T cell differentiation and function during acute viral infection.
    Karla M Viramontes, Melissa N Thone, Julia M DeRogatis, Emily N Neubert, Monique L Henriquez, Jamie-Jean De La Torre, Roberto Tinoco.
      The differentiation and functionality of virus-specific T cells during acute viral infections are crucial for establishing long-term protective immunity. While numerous molecular regulators impacting T cell responses have been uncovered, the role of cellular prion proteins (PrPc) remains underexplored. Here, we investigated the impact of PrPc deficiency on the differentiation and function of virus-specific T cells using the lymphocytic choriomeningitis virus (LCMV) Armstrong acute infection model. Our findings reveal that Prnp-/- mice exhibit a robust expansion of virus-specific CD8+ T cells, with similar activation profiles as wild-type mice during the early stages of infection. However, Prnp-/- mice had higher frequencies and numbers of virus-specific memory CD8+ T cells, along with altered differentiation profiles characterized by increased central and effector memory subsets. Despite similar proliferation rates early during infection, Prnp-/- memory CD8+ T cells had decreased proliferation compared with their wild-type counterparts. Additionally, Prnp-/- mice had higher numbers of cytokine-producing memory CD8+ T cells, indicating a more robust functional response. Furthermore, Prnp-/- mice had increased virus-specific CD4+ T cell responses, suggesting a broader impact of PrPc deficiency on T cell immunity. These results unveil a previously unrecognized role for PrPc in regulating the differentiation, proliferation, and functionality of virus-specific T cells, providing valuable insights into immune system regulation by prion proteins during viral infections.
    Keywords:  LCMV; T cells; memory T cells; prions; viral infection
    DOI:  https://doi.org/10.1093/immhor/vlae002
  4. J Ovarian Res. 2025 Jan 20. 18(1): 9
    Nicotinamide riboside supplementation ameliorates ovarian dysfunction in a PCOS mouse model.
    Zhenye Zhu, Min Lei, Ruizhi Guo, Yining Xu, Yanqing Zhao, Chenlu Wei, Qingling Yang, Yingpu Sun.
      Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility among women of reproductive age, yet the range of effective treatment options remains limited. Our previous study revealed that reduced levels of nicotinamide adenine dinucleotide (NAD+) in ovarian granulosa cells (GCs) of women with PCOS resulted in the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction. However, it is still uncertain whether increasing NAD+ levels in the ovaries could improve ovarian function in PCOS. In this study, we demonstrated that supplementation with the NAD+ precursor nicotinamide riboside (NR) prevented the decrease in ovarian NAD+ levels, normalized estrous cycle irregularities, and enhanced ovulation potential in dehydroepiandrosterone (DHEA)-induced PCOS mice. Moreover, NR supplementation alleviated ovarian fibrosis and enhanced mitochondrial function in ovarian stromal cells of PCOS mice. Furthermore, NR supplementation improved oocyte quality in PCOS mice, as evidenced by reduced abnormal mitochondrial clustering, enhanced mitochondrial membrane potential, decreased ROS levels, reduced spindle abnormality rates, and increased early embryonic development potential in fertilized oocytes. These findings suggest that supplementing with NAD+ precursors could be a promising therapeutic strategy for addressing ovarian infertility associated with PCOS.
    Keywords:  Fibrosis; Mitochondrial; Nicotinamide adenine dinucleotide; Nicotinamide riboside; Ovary; Polycystic ovary syndrome
    DOI:  https://doi.org/10.1186/s13048-025-01596-4
  5. J Orthop Surg Res. 2025 Jan 23. 20(1): 87
    Enhancing the effectiveness of immunotherapy in rheumatoid arthritis by delaying immunosenescence triggered by fibroblast-like synoviocytes.
    Li Zhang, Yang Luo, Hai-Li Shen.
      Rheumatoid arthritis (RA) is a prevalent autoimmune disorder primarily targeting the diarthrodial joints. During the progression of RA, fibroblast-like synoviocytes (FLSs) exhibit tumor-like behavior, including increased proliferation, inflammation mediation, and aggressive phenotypes, leading to bone erosion. Additionally, T cells in RA acquire pro-inflammatory characteristics, exacerbating the inflammatory environment in affected joints and associated tissues. Notably, senescent T cells contribute to inflammation, further accelerating the disease process. Metabolic changes in rheumatoid FLSs not only maintain their tumor-like properties but also trigger inflammatory cascades, particularly affecting T lymphocytes. This review examines the molecular alterations in RA FLSs in the context of systemic immune aging, with a focus on thymic insufficiency-associated T cell senescence, and explores potential therapeutic avenues.
    Keywords:  Fibroblast-like synoviocytes; Immunosenescence; Metabolites/cytokines; Rheumatoid arthritis
    DOI:  https://doi.org/10.1186/s13018-025-05473-0
  6. Front Immunol. 2024 ;15 1515715
    Unfolded protein responses in T cell immunity.
    Wencan Zhang, Xu Cao.
      Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are integral to T cell biology, influencing immune responses and associated diseases. This review explores the interplay between the UPR and T cell immunity, highlighting the role of these cellular processes in T cell activation, differentiation, and function. The UPR, mediated by IRE1, PERK, and ATF6, is crucial for maintaining ER homeostasis and supporting T cell survival under stress. However, the precise mechanisms by which ER stress and the UPR regulate T cell-mediated immunity remain incompletely understood. Emerging evidence suggests that the UPR may be a potential therapeutic target for diseases characterized by T cell dysfunction, such as autoimmune disorders and cancer. Further research is needed to elucidate the complex interactions between ER stress, the UPR, and T cell immunity to develop novel therapeutic strategies for T cell-associated diseases.
    Keywords:  T cell activation; T cell differentiation; endoplasmic reticulum stress; immune regulation; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2024.1515715
  7. J Immunother Cancer. 2025 Jan 16. pii: e010540. [Epub ahead of print]13(1):
    Glut3 overexpression improves environmental glucose uptake and antitumor efficacy of CAR-T cells in solid tumors.
    Wenhao Hu, Feng Li, Yue Liang, Shasha Liu, Shumin Wang, Chunyi Shen, Yuyu Zhao, Hui Wang, Yi Zhang.
       BACKGROUND: Glucose deprivation inhibits T-cell metabolism and function. Glucose levels are low in the tumor microenvironment of solid tumors and insufficient glucose uptake limits the antitumor response of T cells. Furthermore, glucose restriction can contribute to the failure of chimeric antigen receptor T (CAR-T) cell therapy for solid tumors. However, the impact of glucose restriction remains unknown in CAR-T cell therapy.
    METHODS: Glucose transporters were detected and overexpressed in CAR-T cells. The impacts of glucose restriction on CAR-T cells were checked in vitro and in vivo.
    RESULTS: Glucose restriction significantly decreased CAR-T cell activation, effector function, and expansion. CAR-T cells expressed high levels of the glucose transporter Glut1, which has a low affinity for glucose. Overexpression of Glut1 failed to improve CAR-T cell function under glucose-restricted conditions. In contrast, the function and antitumor potential of CAR-T cells was enhanced by the overexpression of Glut3, which has the highest affinity for glucose among the Glut transporter family and is expressed in minor parts of CAR-T cells. Glut3-overexpressing CAR-T cells demonstrated increased tumoricidal efficacy in multiple xenografts and syngenetic mouse models. Furthermore, Glut3 overexpression activated the PI3K/Akt pathway and increased OXPHOS and mitochondrial fitness.
    CONCLUSIONS: We provide a direct and effective approach to enhance low glucose uptake levels by CAR-T cells and improve their antitumor efficacy against solid tumors.
    Keywords:  Chimeric antigen receptor - CAR; Mitochondria; Nutrition; Solid tumor
    DOI:  https://doi.org/10.1136/jitc-2024-010540
  8. Sci Transl Med. 2025 Jan 22. 17(782): eadl6432
    Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice.
    Hongye Wang, Zhaorong Wu, Dan Cui, Linke Bian, Zhigang Zheng, Jiufei Zhu, Haigang Geng, Zhen Sun, Yixiao Pan, Yaoping Shi, Qiaoyong Yi, Zhenyu Song, Yantao Li, Kangjie Shen, Yuan Li, Weiming Shen, Hexin Yan, Ruidong Hao, Minmin Sun, Shuangshung Zhang, Chuanjie Zhang, Haojie Jin, Bo Zhai.
      Chimeric antigen receptor (CAR)-T cell therapies have revolutionized the landscape of cancer treatment, in particular in the context of hematologic malignancies. However, for solid tumors that lack tumor-specific antigens, CAR-T cells can infiltrate and attack nonmalignant tissues expressing the CAR target antigen, leading to on-target, off-tumor toxicity. Severe on-target, off-tumor toxicities have been observed in clinical trials of CAR-T therapy for solid tumors, highlighting the need to address this issue. Here, we demonstrated that targeting the cell adhesion and migration molecules lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) and very late activation antigen 4 (VLA-4; CD49d/CD29) with blocking antibodies reduced the on-target, off-tumor toxicity of CAR-T cells in mice. To translate this observation into improved CAR-T cell therapy, we either knocked out both CD11a and CD49d or knocked down CD11a and CD49d along with PSGL1, another cell adhesion molecule, in CAR-T cells. We found that these modified CAR-T cells exhibited reduced on-target, off-tumor toxicity in vivo without affecting CAR-T cell efficacy. Furthermore, we showed that this approach promoted T cell memory formation and decreased tonic signaling. On the basis of these data, we engineered a human version of these low-toxicity CAR-T cells and further validated the feasibility of this approach in vitro and in vivo. Together, these results provide a potential solution to address the clinical challenge of on-target, off-tumor toxicity in CAR-T therapy.
    DOI:  https://doi.org/10.1126/scitranslmed.adl6432
  9. Methods. 2025 Jan 16. pii: S1046-2023(25)00014-3. [Epub ahead of print]234 286-293
    Innovative PBMC-derived humanized mouse model reveals CD8+ T cell-intrinsic regulation during antitumor immunity.
    Xiaojun Yan, Donglai Wang.
      The PBMC-derived humanized mouse model (PBMC model) may serve as an excellent tool in the field of immunology for both preclinical research and personalized therapeutic strategy development. However, single transplantation of complete PBMCs without modifications prevents the identification of cell type-specific factors that are potentially involved in modulating cell-intrinsic functions for the immune response. Here, we establish an innovative strategy for PBMC model generation, where two-step transplantations coupled with cell type-specific gene manipulation were conducted to evaluate the potential role of CD8+ T cell-intrinsic factors in regulating antitumor immunity toward PDX-based tumors. This method readily yields over 10 % of human CD45+ cells within the PBMCs of humanized mice with high editing efficiency of gene expression in CD8+ T cells that can be subsequently detected in the tumor microenvironment (TME). Our work provides a new method to generate a PBMC-derived humanized mouse model for investigating regulators of interest during antitumor immunity in a cell type-specific manner.
    Keywords:  Antitumor immunity; CD8(+) T cell; Humanized mouse model; PDX
    DOI:  https://doi.org/10.1016/j.ymeth.2025.01.011
  10. Signal Transduct Target Ther. 2025 Jan 22. 10(1): 25
    Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells.
    Gui-Qi Zhu, Zheng Tang, Tian-Hao Chu, Biao Wang, Shi-Ping Chen, Chen-Yang Tao, Jia-Liang Cai, Rui Yang, Wei-Feng Qu, Yi Wang, Qian-Fu Zhao, Run Huang, Meng-Xin Tian, Yuan Fang, Jun Gao, Xiao-Ling Wu, Jian Zhou, Wei-Ren Liu, Zhi Dai, Ying-Hong Shi, Jia Fan.
      Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8+ T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8+ T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41392-024-02118-2
  11. Nature. 2025 Jan 22.
    Immune evasion through mitochondrial transfer in the tumour microenvironment.
    Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi.
      Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08439-0
  12. Front Aging. 2024 ;5 1511370
    Age-associated alterations in immune and inflammatory responses in captive olive baboons (Papio anubis).
    Michele M Mulholland, Bharti P Nehete, Ashley DeLise, Angela M Achorn, Lisa M Pytka, Pramod N Nehete.
       Introduction: Advanced age is a primary risk factor for many chronic diseases and conditions; however, age-related immune dysregulation is not well understood. Animal models, particularly those that resemble human age-related physiological changes, are needed to better understand immunosenescence and to improve health outcomes. Here, we explore the utility of the olive baboon (Papio anubis) in studying age-related changes to the immune system and understanding mechanisms of immunosenescence.
    Methods: We examined immune cell, inflammatory responses, cytokines, and cortisol levels using hematology and flow cytometry, mitogen stimulation, multiplex cytokine assay, and cortisol immunoassay.
    Results and Discussion: Our results reveal significant age effects on numerous immune and inflammatory responses. For instance, adult and aged monkeys exhibited significantly fewer monocytes than young monkeys. After stimulation with Con A and PWM (separately), we found that old baboons had higher INFγ expression compared to young baboons. Similarly, after stimulation with LPS and PWM (separately), we found that old baboons had higher TNFα expression compared to young baboons. These findings suggest that the olive baboon is a suitable model for biogerontology research, immune senescence, and development of vaccines. Though there are phenotypic and functional similarities between baboons and humans, specific differences exist in immune cell expression and immune function of lymphocytes that should be considered for better experimental outcomes in the development of therapeutics and restoring innate and adaptive immune function in aged individuals.
    Keywords:  FLUROSPOT; aging; baboon; cellular immune response; cytokines; elispot; proliferation
    DOI:  https://doi.org/10.3389/fragi.2024.1511370
  13. Aging Cell. 2025 Jan 21. e14483
    Aging and Cancer-Inextricably Linked Across the Lifespan.
    James DeGregori, Katherine J Seidl, Monty Montano.
      Aging (as old man wind) alters the trajectory of cancer (dangerous seas) through changes in the immune system and metabolism (among many others), leading to altered cancer epidemiology, pathogenesis, and therapeutic responses, as represented by the research areas (boats)-artwork by Michael DeGregori.
    DOI:  https://doi.org/10.1111/acel.14483
  14. Nat Biotechnol. 2025 Jan;43(1): 30
    Therapeutic T cells with synthetic gene circuits act locally.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-024-02541-4
  15. JCI Insight. 2025 Jan 23. pii: e180867. [Epub ahead of print]
    Ageing and inflammation limit the induction of SARS-CoV-2-specific CD8+ T cell responses in severe COVID-19.
    Gaëlle Autaa, Laura Papagno, Takuto Nogimori, Andrea Boizard-Moracchini, Daniil Korenkov, Maeva Roy, Koichiro Suzuki, Yuji Masuta, Eoghann White, Sian Llewellyn-Lacey, Yasuo Yoshioka, Francesco Nicoli, David A Price, Julie Dechanet-Merville, Takuya Yamamoto, Isabelle Pellegrin, Victor Appay.
      CD8+ T cells are critical for immune protection against severe COVID-19 during acute infection with SARS-CoV-2. However, the induction of antiviral CD8+ T cell responses varies substantially among infected people, and a better understanding of the mechanisms that underlie such immune heterogeneity is required for pandemic preparedness and risk stratification. In this study, we analyzed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in relation to age, clinical status, and inflammation among patients infected primarily during the initial wave of the pandemic in France or Japan. We found that age-related contraction of the naive lymphocyte pool and systemic inflammation were associated with suboptimal SARS-CoV-2-specific CD4+ and, even more evidently, CD8+ T cell immunity in patients with acute COVID-19. No such differences were observed for humoral immune responses targeting the spike protein of SARS-CoV-2. We also found that the proinflammatory cytokine IL-18, concentrations of which were significantly elevated among patients with severe disease, suppressed the de novo induction and memory recall of antigen-specific CD8+ T cells, including those directed against SARS-CoV-2. These results potentially explain the vulnerability of older adults to infections that elicit a profound inflammatory response, exemplified by acute COVID-19.
    Keywords:  Aging; COVID-19; Cellular immune response; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.180867
  16. Nature. 2025 Jan 22.
    Cancer cells 'poison' the immune system with tainted mitochondria.
    Asher Mullard.
      
    Keywords:  Cancer; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-00176-2
  17. Nat Med. 2025 Jan 20.
    Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.
    Julie K Jadlowsky, Elizabeth O Hexner, Amy Marshall, Stephan A Grupp, Noelle V Frey, James L Riley, Elizabeth Veloso, Holly McConville, Walter Rogal, Cory Czuczman, Wei-Ting Hwang, Yimei Li, Rachel M Leskowitz, Olivia Farrelly, Jayashree Karar, Shannon Christensen, Julie Barber-Rotenberg, Avery Gaymon, Naomi Aronson, Wendy Bernstein, Jan Joseph Melenhorst, Aoife M Roche, John K Everett, Sonja A Zolnoski, Alexander G McFarland, Shantan Reddy, Angelina Petrichenko, Emma J Cook, Carole Lee, Vanessa E Gonzalez, Kathleen Alexander, Irina Kulikovskaya, Ángel Ramírez-Fernández, Janna C Minehart, Marco Ruella, Saar I Gill, Stephen J Schuster, Adam D Cohen, Alfred L Garfall, Payal D Shah, David L Porter, Shannon L Maude, Bruce L Levine, Donald L Siegel, Anne Chew, Stephen McKenna, Lester Lledo, Megan M Davis, Gabriela Plesa, Friederike Herbst, Edward A Stadtmauer, Pablo Tebas, Amanda DiNofia, Andrew Haas, Naomi B Haas, Regina Myers, Donald M O'Rourke, Jakub Svoboda, Janos L Tanyi, Richard Aplenc, Jeffrey M Jacobson, Andrew H Ko, Roger B Cohen, Carl H June, Frederic D Bushman, Joseph A Fraietta.
      Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer. Eighteen patients (2.3%) developed secondary malignancies after treatment, with a median onset of 1.94 years (range: 51 d to 14 years). Where possible, incident tumor samples were analyzed for vector copy number, revealing no evidence of high-level marking or other indications of insertional mutagenesis. One T cell lymphoma was detected, but malignant T cells were not marked by vector integration. Analysis of vector integration sites in 176 patients revealed no pathological insertions linked to secondary malignancies, although, in some cases, integration in or near specific genes, including tumor suppressor genes, was associated with modest clonal expansion and sustained T cell persistence. These findings highlight the safety of engineered T cell therapies.
    DOI:  https://doi.org/10.1038/s41591-024-03478-6
  18. Annu Rev Pathol. 2025 Jan;20(1): 483-509
    Immune Dysregulation in Obesity.
    Zewen Jiang, Chihiro Tabuchi, Sarah G Gayer, Sagar P Bapat.
      The immune system plays fundamental roles in maintaining physiological homeostasis. With the increasing prevalence of obesity-a state characterized by chronic inflammation and systemic dyshomeostasis-there is growing scientific and clinical interest in understanding how obesity reshapes immune function. In this review, we propose that obesity is not merely an altered metabolic state but also a fundamentally altered immunological state. We summarize key seminal and recent findings that elucidate how obesity influences immune function, spanning its classical role in microbial defense, its contribution to maladaptive inflammatory diseases such as asthma, and its impact on antitumor immunity. We also explore how obesity modulates immune function within tissue parenchyma, with a particular focus on the role of T cells in adipose tissue. Finally, we consider areas for future research, including investigation of the durable aspects of obesity on immunological function even after weight loss, such as those observed with glucagon-like peptide-1 (GLP-1) receptor agonist treatment. Altogether, this review emphasizes the critical role of systemic metabolism in shaping immune cell functions, with profound implications for tissue homeostasis across various physiological contexts.
    Keywords:  GLP-1 receptor agonists; PPARγ; adipose tissue immunology; high-fat diet; immune system; inflammatory disease; microbiome; obesity; tumor immunity
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-051222-015350
  19. Front Aging. 2024 ;5 1526230
    Hallmarks of aging: middle-aging hypovascularity, tissue perfusion and nitric oxide perspective on healthspan.
    Teow J Phua.
      Aging is a complex process marked by various changes at both cellular and systemic levels, impacting the functioning and lifespan of organisms. Over time, researchers have pinpointed several significant hallmarks of aging that lead to the gradual deterioration of tissue function, regulation, and homeostasis associated with aging in humans. Despite this, the intricate interactions and cumulative effects of these hallmarks are still mostly uncharted territory. Understanding this complex web is a major challenge in Geroscience, yet it is crucial for developing effective strategies that promote healthy aging, reduce medical costs, and ensure the sustainability of health systems. Gaining insights in this area is essential for creating interventions that can slow the aging process, enhance healthspan, and decrease the likelihood of age-related diseases. The integration of knowledge from various fields concerning the middle-aging nitric oxide (NO)-mediated hypovascularity hypoxia hemodynamic hypothesis points to a systems-based approach to the biological hallmarks of aging. Key evidence suggests a systemic connection between the endocrine system (specifically sex hormones), endogenous NO deficiency, and the vascular system, which serves as a network of microvascular structures crucial for tissue perfusion functions at cellular level. These processes also involve oxidative stress and inflammation triggered by hypoxia.
    Keywords:  aging hallmarks; causal inference; geroscience; healthspan; nitric oxide; tissue perfusion; triangulation of evidence; vascular aging
    DOI:  https://doi.org/10.3389/fragi.2024.1526230
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