bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–03–12
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. TRIB2 safeguards naive T cell homeostasis during aging.
  2. The autophagy-NAD axis in longevity and disease.
  3. TIGIT signaling and its influence on T cell metabolism and immune cell function in the tumor microenvironment.
  4. T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications.
  5. Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.
  6. Targeting regulatory T cell metabolism in disease: novel therapeutic opportunities.
  7. TCF-1 Is Required for CD4 T Cell Persistence Functions during AlloImmunity.
  8. IL18 at the Crossroads between Chronic Inflammation and T-cell Exhaustion in Pancreatic Cancer.
  9. Train your T cells: how skeletal muscles and T cells keep each other fit during aging.
  10. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.
  11. The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment.
  12. Characterization of Dendritic Cell Metabolism by Flow Cytometry.
  13. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
  14. Glutamine Metabolism Underlies the Functional Similarity of T Cells between Nile Tilapia and Tetrapod.
  15. Mitochondrial molecule controls inflammation.
  16. Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors.
  17. A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.
  18. Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.
  19. The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model.
  1. Cell Rep. 2023 Mar 06. pii: S2211-1247(23)00206-1. [Epub ahead of print]42(3): 112195
    TRIB2 safeguards naive T cell homeostasis during aging.
    Wenqiang Cao, Ines Sturmlechner, Huimin Zhang, Jun Jin, Bin Hu, Rohit R Jadhav, Fengqin Fang, Cornelia M Weyand, Jörg J Goronzy.
      Naive CD4+ T cells are more resistant to age-related loss than naive CD8+ T cells, suggesting mechanisms that preferentially protect naive CD4+ T cells during aging. Here, we show that TRIB2 is more abundant in naive CD4+ than CD8+ T cells and counteracts quiescence exit by suppressing AKT activation. TRIB2 deficiency increases AKT activity and accelerates proliferation and differentiation in response to interleukin-7 (IL-7) in humans and during lymphopenia in mice. TRIB2 transcription is controlled by the lineage-determining transcription factors ThPOK and RUNX3. Ablation of Zbtb7b (encoding ThPOK) and Cbfb (obligatory RUNT cofactor) attenuates the difference in lymphopenia-induced proliferation between naive CD4+ and CD8+ cells. In older adults, ThPOK and TRIB2 expression wanes in naive CD4+ T cells, causing loss of naivety. These findings assign TRIB2 a key role in regulating T cell homeostasis and provide a model to explain the lesser resilience of CD8+ T cells to undergo changes with age.
    Keywords:  CP: Immunology; T cell aging; T cell homeostasis; TRIB2; immunosenescence; naive T cells; virtual memory T cell
    DOI:  https://doi.org/10.1016/j.celrep.2023.112195
  2. Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]
    The autophagy-NAD axis in longevity and disease.
    Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
    Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
  3. Front Oncol. 2023 ;13 1060112
    TIGIT signaling and its influence on T cell metabolism and immune cell function in the tumor microenvironment.
    Nouria Jantz-Naeem, Romy Böttcher-Loschinski, Katrin Borucki, Marisa Mitchell-Flack, Martin Böttcher, Burkhart Schraven, Dimitrios Mougiakakos, Sascha Kahlfuss.
      One of the key challenges for successful cancer therapy is the capacity of tumors to evade immune surveillance. Tumor immune evasion can be accomplished through the induction of T cell exhaustion via the activation of various immune checkpoint molecules. The most prominent examples of immune checkpoints are PD-1 and CTLA-4. Meanwhile, several other immune checkpoint molecules have since been identified. One of these is the T cell immunoglobulin and ITIM domain (TIGIT), which was first described in 2009. Interestingly, many studies have established a synergistic reciprocity between TIGIT and PD-1. TIGIT has also been described to interfere with the energy metabolism of T cells and thereby affect adaptive anti-tumor immunity. In this context, recent studies have reported a link between TIGIT and the hypoxia-inducible factor 1-α (HIF1-α), a master transcription factor sensing hypoxia in several tissues including tumors that among others regulates the expression of metabolically relevant genes. Furthermore, distinct cancer types were shown to inhibit glucose uptake and effector function by inducing TIGIT expression in CD8+ T cells, resulting in an impaired anti-tumor immunity. In addition, TIGIT was associated with adenosine receptor signaling in T cells and the kynurenine pathway in tumor cells, both altering the tumor microenvironment and T cell-mediated immunity against tumors. Here, we review the most recent literature on the reciprocal interaction of TIGIT and T cell metabolism and specifically how TIGIT affects anti-tumor immunity. We believe understanding this interaction may pave the way for improved immunotherapy to treat cancer.
    Keywords:  T cells; cancer; metabolism; microenviroment; therapy
    DOI:  https://doi.org/10.3389/fonc.2023.1060112
  4. Front Immunol. 2023 ;14 1104771
    T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications.
    Xiaoxia Chi, Shahang Luo, Peng Ye, Wei-Lun Hwang, Jong-Ho Cha, Xiuwen Yan, Wen-Hao Yang.
      T cells play a crucial role in the regulation of immune response and are integral to the efficacy of cancer immunotherapy. Because immunotherapy has emerged as a promising treatment for cancer, increasing attention has been focused on the differentiation and function of T cells in immune response. In this review, we describe the research progress on T-cell exhaustion and stemness in the field of cancer immunotherapy and summarize advances in potential strategies to intervene and treat chronic infection and cancer by reversing T-cell exhaustion and maintaining and increasing T-cell stemness. Moreover, we discuss therapeutic strategies to overcome T-cell immunodeficiency in the tumor microenvironment and promote continuous breakthroughs in the anticancer activity of T cells.
    Keywords:  TSCM; cancer immunotherapy; chronic antigenic stimulation; exhaustion; stemness
    DOI:  https://doi.org/10.3389/fimmu.2023.1104771
  5. J Hepatol. 2023 Mar 07. pii: S0168-8278(23)00167-8. [Epub ahead of print]
    Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.
    Ilaria Montali, Camilla Ceccatelli Berti, Marco Morselli, Greta Acerbi, Valeria Barili, Giuseppe Pedrazzi, Barbara Montanini, Carolina Boni, Arianna Alfieri, Marco Pesci, Alessandro Loglio, Elisabetta Degasperi, Marta Borghi, Riccardo Perbellini, Amalia Penna, Diletta Laccabue, Marzia Rossi, Andrea Vecchi, Camilla Tiezzi, Valentina Reverberi, Chiara Boarini, Gianluca Abbati, Marco Massari, Pietro Lampertico, Gabriele Missale, Carlo Ferrari, Paola Fisicaro.
       BACKGROUND AND AIMS: In chronic HBV infection elevated ROS levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. Aim of this study was to understand how these defects are mechanistically interconnected in order to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies.
    METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signaling alterations and improvement of anti-viral T cell functions by the NAD precursor NMN and by CD38 inhibition was assessed.
    RESULTS: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function.
    CONCLUSIONS: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore anti-viral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection.
    Keywords:  DNA repair; NAD; immune-modulation; senescence
    DOI:  https://doi.org/10.1016/j.jhep.2023.02.035
  6. Eur J Immunol. 2023 Mar 09. e2250002
    Targeting regulatory T cell metabolism in disease: novel therapeutic opportunities.
    Torin Halvorson, Karoliina Tuomela, Megan K Levings.
      Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti-tumour immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody-mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function. This article is protected by copyright. All rights reserved.
    Keywords:  autoimmunity; immunotherapy; metabolism; regulatory T cell; transplantation
    DOI:  https://doi.org/10.1002/eji.202250002
  7. Int J Mol Sci. 2023 Feb 21. pii: 4326. [Epub ahead of print]24(5):
    TCF-1 Is Required for CD4 T Cell Persistence Functions during AlloImmunity.
    Mahinbanu Mammadli, Liye Suo, Jyoti Misra Sen, Mobin Karimi.
      The transcription factor T cell factor-1 (TCF-1) is encoded by Tcf7 and plays a significant role in regulating immune responses to cancer and pathogens. TCF-1 plays a central role in CD4 T cell development; however, the biological function of TCF-1 on mature peripheral CD4 T cell-mediated alloimmunity is currently unknown. This report reveals that TCF-1 is critical for mature CD4 T cell stemness and their persistence functions. Our data show that mature CD4 T cells from TCF-1 cKO mice did not cause graft versus host disease (GvHD) during allogeneic CD4 T cell transplantation, and donor CD4 T cells did not cause GvHD damage to target organs. For the first time, we showed that TCF-1 regulates CD4 T cell stemness by regulating CD28 expression, which is required for CD4 stemness. Our data showed that TCF-1 regulates CD4 effector and central memory formation. For the first time, we provide evidence that TCF-1 differentially regulates key chemokine and cytokine receptors critical for CD4 T cell migration and inflammation during alloimmunity. Our transcriptomic data uncovered that TCF-1 regulates critical pathways during normal state and alloimmunity. Knowledge acquired from these discoveries will enable us to develop a target-specific approach for treating CD4 T cell-mediated diseases.
    Keywords:  CD4 T cell serum level cytokine production; CD4 T cells stemness; TCF-1; alloimmunity
    DOI:  https://doi.org/10.3390/ijms24054326
  8. Cancer Immunol Res. 2023 Mar 10. OF1
    IL18 at the Crossroads between Chronic Inflammation and T-cell Exhaustion in Pancreatic Cancer.
    Ingunn M Stromnes.
      Chronic inflammation and immune evasion are hallmarks of cancer. Cancer promotes T-cell differentiation toward an exhausted, or dysfunctional state, which contributes to immune evasion. In this issue, Lutz and colleagues show that the proinflammatory cytokine IL18 correlates with poor patient prognosis and promotes CD8+ T-cell exhaustion in pancreatic cancer by enhancing IL2R signaling. This link between proinflammatory cytokines and T-cell exhaustion elucidates consequences of modulating cytokine signaling during cancer immunotherapy. See related article by Lutz et al. (1) .
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0145
  9. Brain Behav Immun. 2023 Mar 07. pii: S0889-1591(23)00063-6. [Epub ahead of print]
    Train your T cells: how skeletal muscles and T cells keep each other fit during aging.
    Helena Slaets, Lena Fonteyn, Bert O Eijnde, Niels Hellings.
      Frailty and a failing immune system lead to significant morbidities in the final years of life and bring along a significant burden on healthcare systems. The good news is that regular exercise provides an effective countermeasure for losing muscle tissue when we age while supporting proper immune system functioning. For a long time, it was assumed that exercise-induced immune responses are predominantly mediated by myeloid cells, but it has become evident that they receive important help from T lymphocytes. Skeletal muscles and T cells interact, not only in muscle pathology but also during exercise. In this review article, we provide an overview of the most important aspects of T cell senescence and discuss how these are modulated by exercise. In addition, we describe how T cells are involved in muscle regeneration and growth. A better understanding of the complex interactions between myocytes and T cells throughout all stages of life provides important insights needed to design strategies that effectively combat the wave of age-related diseases the world is currently faced with.
    Keywords:  T cells; aging; exercise; immune senescence; muscle; sarcopenia
    DOI:  https://doi.org/10.1016/j.bbi.2023.03.006
  10. Cell Metab. 2023 Mar 06. pii: S1550-4131(23)00049-9. [Epub ahead of print]
    Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.
    Carina B Nava Lauson, Silvia Tiberti, Paola A Corsetto, Federica Conte, Punit Tyagi, Markus Machwirth, Stefan Ebert, Alessia Loffreda, Lukas Scheller, Dalia Sheta, Zeinab Mokhtari, Timo Peters, Ayush T Raman, Francesco Greco, Angela M Rizzo, Andreas Beilhack, Giovanni Signore, Nicola Tumino, Paola Vacca, Liam A McDonnell, Andrea Raimondi, Philip D Greenberg, Johannes B Huppa, Simone Cardaci, Ignazio Caruana, Simona Rodighiero, Luigi Nezi, Teresa Manzo.
      The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.
    Keywords:  CD8 T cells; adoptive T cell therapy; linoleic acid; lipid metabolism; metabolic fitness
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.013
  11. Cancers (Basel). 2023 Mar 03. pii: 1588. [Epub ahead of print]15(5):
    The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment.
    Maik Luu, Burkhard Schütz, Matthias Lauth, Alexander Visekruna.
      Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.
    Keywords:  cancer immunotherapy; commensal bacteria; intratumoral microbiota; microbiota-derived metabolites; oncobiome; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers15051588
  12. Methods Mol Biol. 2023 ;2618 219-237
    Characterization of Dendritic Cell Metabolism by Flow Cytometry.
    Eline C Brombacher, Thiago A Patente, Marjolein Quik, Bart Everts.
      In response to different stimuli, dendritic cells (DCs) undergo metabolic reprogramming to support their function. Here we describe how fluorescent dyes and antibody-based approaches can be used to assess various metabolic parameters of DCs including glycolysis, lipid metabolism, mitochondrial activity, and the activity of important sensors and regulators of cellular metabolism, mTOR and AMPK. These assays can be performed using standard flow cytometry and will allow for the determination of metabolic properties of DC populations at single-cell level and to characterize metabolic heterogeneity within them.
    Keywords:  Dendritic cells; Flow cytometry; Glucose; Lipids; Metabolism; Mitochondria; ROS
    DOI:  https://doi.org/10.1007/978-1-0716-2938-3_16
  13. Nat Aging. 2023 Feb;3(2): 157-161
    Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
    Brandon J Berry, Anežka Vodičková, Annika Müller-Eigner, Chen Meng, Christina Ludwig, Matt Kaeberlein, Shahaf Peleg, Andrew P Wojtovich.
      Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-022-00340-7
  14. Adv Sci (Weinh). 2023 Mar 08. e2201164
    Glutamine Metabolism Underlies the Functional Similarity of T Cells between Nile Tilapia and Tetrapod.
    Kang Li, Xiumei Wei, Xinying Jiao, Wenhai Deng, Jiaqi Li, Wei Liang, Yu Zhang, Jialong Yang.
      As the lowest organisms possessing T cells, fish are instrumental for understanding T cell evolution and immune defense in early vertebrates. This study established in Nile tilapia models suggests that T cells play a critical role in resisting Edwardsiella piscicida infection via cytotoxicity and are essential for IgM+ B cell response. CD3 and CD28 monoclonal antibody crosslinking reveals that full activation of tilapia T cells requires the first and secondary signals, while Ca2+ -NFAT, MAPK/ERK, NF-κB, and mTORC1 pathways and IgM+ B cells collectively regulate T cell activation. Thus, despite the large evolutionary distance, tilapia and mammals such as mice and humans exhibit similar T cell functions. Furthermore, it is speculated that transcriptional networks and metabolic reprogramming, especially c-Myc-mediated glutamine metabolism triggered by mTORC1 and MAPK/ERK pathways, underlie the functional similarity of T cells between tilapia and mammals. Notably, tilapia, frogs, chickens, and mice utilize the same mechanisms to facilitate glutaminolysis-regulated T cell responses, and restoration of the glutaminolysis pathway using tilapia components rescues the immunodeficiency of human Jurkat T cells. Thus, this study provides a comprehensive picture of T cell immunity in tilapia, sheds novel perspectives for understanding T cell evolution, and offers potential avenues for intervening in human immunodeficiency.
    Keywords:  T cells; evolution; functional similarity; glutamine metabolism; tilapia
    DOI:  https://doi.org/10.1002/advs.202201164
  15. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  16. Oncoimmunology. 2023 ;12(1): 2182058
    Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors.
    Jian Ding, Sarah Guyette, Brett Schrand, Jessica Geirut, Holly Horton, Guangwu Guo, Greg Delgoffe, Ashley Menk, Patrick A Baeuerle, Robert Hofmeister, Robert Tighe.
      T cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.
    Keywords:  Chimeric antigen receptor; T cell Receptor Fusion Construct (TRuC®) T cells; T cell receptor; mesothelin; metabolism
    DOI:  https://doi.org/10.1080/2162402X.2023.2182058
  17. Acta Pharm Sin B. 2023 Feb;13(2): 775-786
    A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.
    Qianhua Feng, Yutong Hao, Shuaiqi Yang, Xiaomin Yuan, Jing Chen, Yuying Mei, Lanlan Liu, Junbiao Chang, Zhenzhong Zhang, Lei Wang.
      The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.
    Keywords:  Cerium metal–organic framework; Drug delivery; Glutamine metabolism; Immunogenic tumor cell death; Immunotherapy; Lactate oxidase; Metabolic intervention; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.apsb.2022.10.021
  18. Geroscience. 2023 Mar 06.
    Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.
    Brandon J Berry, Evan Mjelde, Fatima Carreno, Kathryn Gilham, Emily J Hanson, Emily Na, Matt Kaeberlein.
      Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψm) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψm is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψm during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψm declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψm blocked the longevity and health benefits of DR. Genetic perturbation of Δψm and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψm is a critical factor for health and longevity in response to DR.
    Keywords:  Aging; Bioenergetics; Calorie restriction; Fasting; Metabolism; Mitochondrial uncoupling
    DOI:  https://doi.org/10.1007/s11357-023-00766-w
  19. J Osteoporos. 2023 ;2023 5572754
    The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model.
    William S Hambright, Xiaodong Mu, Xueqin Gao, Ping Guo, Yohei Kawakami, John Mitchell, Michael Mullen, Anna-Laura Nelson, Chelsea Bahney, Haruki Nishimura, Justin Hellwinkel, Andrew Eck, Johnny Huard.
      Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics-compounds which selectively target and kill senescent cells-have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24-/- (Z24-/-) progeria murine system for Hutchinson-Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24-/- model. Furthermore, the overt bone density loss observed in the Z24-/- model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the "geroscience hypothesis," these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.
    DOI:  https://doi.org/10.1155/2023/5572754
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