bims-imseme 2024-09-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–09–15
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The molecular landscape of T cell exhaustion in the tumor microenvironment and reinvigoration strategies.
A pinch of salt boosts T cell function.
Seno-antigen-pulsed dendritic cell vaccine induce anti-aging immunity to improve adipose tissue senescence and metabolic abnormalities.
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.
IL-2 delivery to CD8+ T cells during infection requires MRTF/SRF-dependent gene expression and cytoskeletal dynamics.
Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells.
Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function.
Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation.
Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy.
Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.
Biological Functions and Therapeutic Potential of NAD+ Metabolism in Gynecological Cancers.
Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.
Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption.
Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.
Intracellular zinc protects tumours from T cell-mediated cytotoxicity.

Int Rev Immunol. 2024 Sep 11. 1-22

The molecular landscape of T cell exhaustion in the tumor microenvironment and reinvigoration strategies.

Mahsa Heidari-Foroozan, Alaleh Rezalotfi, Nima Rezaei.

  Immunotherapy has emerged as a promising therapeutic approach for cancer treatment by harnessing the immune system to target cancer cells. However, the efficacy of immunotherapy is hindered by the tumor microenvironment (TME), comprising regulatory T cells (Tregs), macrophages, myeloid-derived suppressor cells (MDSCs), neutrophils, soluble factors (TGF-β, IL-35, IL-10), and hypoxia. These components interact with inhibitory receptors (IRs) on T cells, leading to alterations in T cell transcriptomes, epigenomes, and metabolism, ultimately resulting in T cell exhaustion and compromising the effectiveness of immunotherapy. T cell exhaustion occurs in two phases: pre-exhaustion and exhaustion. Pre-exhausted T cells exhibit reversibility and distinct molecular properties compared to terminally exhausted T cells. Understanding these differences is crucial for designing effective interventions. This comprehensive review summarizes the characteristics of pre-exhausted and exhausted T cells and elucidates the influence of TME components on T cell activity, transcriptomes, epigenomes, and metabolism, ultimately driving T cell exhaustion in cancer. Additionally, potential intervention strategies for reversing exhaustion are discussed. By gaining insights into the mechanisms underlying T cell exhaustion and the impact of the TME, this review aims to inform the development of innovative approaches for combating T cell exhaustion and enhancing the efficacy of immunotherapy in cancer treatment.

Keywords:  Immunotherapy; T cell exhaustion; neoplasms; pre-exhausted T cells; tumor microenvironment

DOI:  https://doi.org/10.1080/08830185.2024.2401352
Nat Immunol. 2024 Sep 09.

A pinch of salt boosts T cell function.

Karina L Hajdu, Lorène Rousseau, Ping-Chih Ho.

DOI: https://doi.org/10.1038/s41590-024-01946-2
Biomed Pharmacother. 2024 Sep 10. pii: S0753-3322(24)01318-0. [Epub ahead of print]179 117433

Seno-antigen-pulsed dendritic cell vaccine induce anti-aging immunity to improve adipose tissue senescence and metabolic abnormalities.

Yin Cao, Xiaoxue Du, Jiahong Yu, Ying Wang, Xinliang Jin, Baijian Gu, Qiliang Yin.

  Anti-aging immunity induced by vaccines was recently reported to enable the elimination of senescent cells. However, the initial immune response to vaccination declines with age, and there is evidence that elderly dendritic cells (DCs) have a reduced capacity to stimulate T cells. Identification of alternative anti-aging vaccine is therefore warranted. Here, we developed a DC vaccine that delivers a cationic protein (CP) fused with the seno-antigen peptides Gpnmb (Gpnmb-CP) into DCs. The Gpnmb-CP-pulsed DC vaccine (Gpnmb-CP-DC) efficiently presented antigens and activated CD8+ T cells, leading to enhanced immune cytotoxicity and memory responses in CD8+ T cells. Thus, the targeted anti-aging immunity triggered by Gpnmb-CP-DC has the ability to selectively eliminate senescent adipocytes and effectively improve age-related metabolic abnormalities in both high-fat diet (HFD)-induced young and aged mice models, as well as in natural aging mouse model. In contrast, the Gpnmb-CP protein vaccine exhibits minimal efficacy in aged mice model. Furthermore, we observed a decreased phagocytic capacity for antigens in aging DCs, accompanied by an upregulation of the immune checkpoint PDL1 expression and a noticeable decline in activated CD8+ T cell. Hence, Gpnmb-CP-DC emerges as a promising vaccine candidate, demonstrating the capacity to induce potent anti-aging immunity, mitigating adipose tissue senescence and metabolic abnormalities, while resilient to the senescent environment of the organism.

Keywords:  Dendritic cell vaccine; Metabolic abnormalities; Senescence; Seno-antigen

DOI:  https://doi.org/10.1016/j.biopha.2024.117433
bioRxiv. 2024 Aug 27. pii: 2024.08.26.609422. [Epub ahead of print]

IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.

Zarina Brune, Ailing Lu, Matthew Moss, Leianna Brune, Amanda Huang, Bharati Matta, Betsy J Barnes.

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5. T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.

DOI: https://doi.org/10.1101/2024.08.26.609422
Nat Commun. 2024 Sep 11. 15(1): 7956

IL-2 delivery to CD8+ T cells during infection requires MRTF/SRF-dependent gene expression and cytoskeletal dynamics.

Diane Maurice, Patrick Costello, Jessica Diring, Francesco Gualdrini, Bruno Frederico, Richard Treisman.

Paracrine IL-2 signalling drives the CD8 + T cell expansion and differentiation that allow protection against viral infections, but the underlying molecular events are incompletely understood. Here we show that the transcription factor SRF, a master regulator of cytoskeletal gene expression, is required for effective IL-2 signalling during L. monocytogenes infection. Acting cell-autonomously with its actin-regulated cofactors MRTF-A and MRTF-B, SRF is dispensible for initial TCR-mediated CD8+ T cell proliferation, but is required for sustained IL-2 dependent CD8+ effector T cell expansion, and persistence of memory cells. Following TCR activation, Mrtfab-null CD8+ T cells produce IL-2 normally, but homotypic clustering is impaired both in vitro and in vivo. Expression of cytoskeletal structural and regulatory genes, most notably actins, is defective in Mrtfab-null CD8+ T cells. Activation-induced cell clustering in vitro requires F-actin assembly, and Mrtfab-null cell clusters are small, contain less F-actin, and defective in IL-2 retention. Clustering of Mrtfab-null cells can be partially restored by exogenous actin expression. IL-2 mediated CD8+ T cell proliferation during infection thus depends on the control of cytoskeletal dynamics and actin gene expression by MRTF-SRF signalling.

DOI: https://doi.org/10.1038/s41467-024-52230-8
Nat Commun. 2024 Sep 06. 15(1): 7789

Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells.

Tereza Dvorakova, Veronica Finisguerra, Matteo Formenti, Axelle Loriot, Loubna Boudhan, Jingjing Zhu, Benoit J Van den Eynde.

While adoptive cell therapy has shown success in hematological malignancies, its potential against solid tumors is hindered by an immunosuppressive tumor microenvironment (TME). In recent years, members of the hypoxia-inducible factor (HIF) family have gained recognition as important regulators of T-cell metabolism and function. The role of HIF signalling in activated CD8 T cell function in the context of adoptive cell transfer, however, has not been explored in full depth. Here we utilize CRISPR-Cas9 technology to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, thereby stabilizing HIF-1 signalling, in CD8 T cells that have already undergone differentiation and activation, modelling the T cell phenotype utilized in clinical settings. We observe a significant boost in T-cell activation and effector functions following PHD2/3 deletion, which is dependent on HIF-1α, and is accompanied by an increased glycolytic flux. This improvement in CD8 T cell performance translates into an enhancement in tumor response to adoptive T cell therapy in mice, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. These findings hold promise for advancing CD8 T-cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.

DOI: https://doi.org/10.1038/s41467-024-51782-z
Proc Natl Acad Sci U S A. 2024 Sep 17. 121(38): e2322929121

Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function.

Cara A Reynolds, Sandra Pelka, Floralba Gjergjova, Inmaculada Tasset, Rabia R Khawaja, Kristen Lindenau, Gregory J Krause, Evripidis Gavathiotis, Ana Maria Cuervo, Fernando Macian.

  Chaperone-mediated autophagy (CMA) is a selective form of autophagy that contributes to the maintenance of cellular homeostasis. CMA activity declines with age in most tissues and systems, including the immune system, due to a reduction in levels of lysosome-associated membrane protein type 2A (LAMP2A), an essential CMA component. In this study, we show that overexpressing a copy of hLAMP2A within T cells since middle-age can prevent some of their age-associated loss of function. Our data support the idea that preserving LAMP2A expression with age through genetic means leads to enhanced proliferative responses, decreased number of regulatory T cell populations, and down-regulated expression of inhibitory receptors by T cells. During aging, elevated numbers of these immunosuppressive T cell populations significantly contribute to the age-associated downregulation of T cell responses. Using comparative proteomics, we confirm that preservation of CMA activity in old mice prevents age-related changes in both the resting and the activated T cell proteome. We also explore the effect of using first-in-class small molecule activators of CMA and demonstrate improved T cell response upon their administration to old mice. We conclude that sustaining CMA activity constitutes a potentially viable therapeutic approach to improving T cell function with age.

Keywords:  T cells; aging; autophagy; gerotherapeutics; immunosenescence

DOI:  https://doi.org/10.1073/pnas.2322929121
Nat Cell Biol. 2024 Sep 11.

Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.

Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

DOI: https://doi.org/10.1038/s41556-024-01503-x
Cell Metab. 2024 Aug 29. pii: S1550-4131(24)00332-2. [Epub ahead of print]

SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation.

Wenhui Liu, Danming You, Jiayang Lin, Huren Zou, Lei Zhang, Shenjian Luo, Youwen Yuan, Zhiyi Wang, Jingwen Qi, Weiwei Wang, Xueru Ye, Xiaoyu Yang, Yajuan Deng, Fei Teng, Xiaojun Zheng, Yuhao Lin, Zhiwei Huang, Yan Huang, Zhi Yang, Xuan Zhou, Yanan Zhang, Ruxin Chen, Lingling Xu, Jin Li, Wei Yang, Huijie Zhang.

  During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.

Keywords:  BDH1; CD8(+) T cell; SGLT2 inhibitor; ketogenesis; metabolic dysfunction-associated steatohepatitis

DOI:  https://doi.org/10.1016/j.cmet.2024.08.005
Sci Adv. 2024 Sep 13. 10(37): eadi7764

Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy.

Yun Liu, Chen Xu, Li Zhang, Guiqin Xu, Zhaojuan Yang, Lvzhu Xiang, Kun Jiao, Zehong Chen, Xiaoren Zhang, Yongzhong Liu.

Tumor cell-originated events prevent efficient antitumor immune response and limit the application of anti-PD1 checkpoint immunotherapy. We show that syndecan-1 (SDC1) has a critical role in the regulation of T cell-mediated control of tumor growth. SDC1 inhibition increases the permeation of CD8+ T cells into tumors and triggers CD8+ T cell-mediated control of tumor growth, accompanied by increased proportions of progenitor-exhausted and effector-like CD8+ T cells. SDC1 deficiency alters multiple signaling events in tumor cells, including enhanced IFN-γ-STAT1 signaling, and augments antigen presentation and sensitivity to T cell-mediated cytotoxicity. Combinatory inhibition of SDC1 markedly potentiates the therapeutic effects of anti-PD1 in inhibiting tumor growth. Consistently, the findings are supported by the data from human tumors showing that SDC1 expression negatively correlates with T cell presence in tumor tissues and the response to immune checkpoint blockade therapy. Our findings suggest that SDC1 inhibits antitumor immunity, and that targeting SDC1 may promote anti-PD1 response for cancer treatment.

DOI: https://doi.org/10.1126/sciadv.adi7764
Sci Immunol. 2024 Sep 13. 9(99): eadi3487

Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.

Duncan M Morgan, Brendan L Horton, Vidit Bhandarkar, Richard Van, Teresa Dinter, Maria Zagorulya, J Christopher Love, Stefani Spranger.

Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8+ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.

DOI: https://doi.org/10.1126/sciimmunol.adi3487
Cancers (Basel). 2024 Sep 05. pii: 3085. [Epub ahead of print]16(17):

Biological Functions and Therapeutic Potential of NAD+ Metabolism in Gynecological Cancers.

Subin Myong, Anh Quynh Nguyen, Sridevi Challa.

  Nicotinamide adenine dinucleotide (NAD+) is an important cofactor for both metabolic and signaling pathways, with the dysregulation of NAD+ levels acting as a driver for diseases such as neurodegeneration, cancers, and metabolic diseases. NAD+ plays an essential role in regulating the growth and progression of cancers by controlling important cellular processes including metabolism, transcription, and translation. NAD+ regulates several metabolic pathways such as glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and fatty acid oxidation by acting as a cofactor for redox reactions. Additionally, NAD+ acts as a cofactor for ADP-ribosyl transferases and sirtuins, as well as regulating cellular ADP-ribosylation and deacetylation levels, respectively. The cleavage of NAD+ by CD38-an NAD+ hydrolase expressed on immune cells-produces the immunosuppressive metabolite adenosine. As a result, metabolizing and maintaining NAD+ levels remain crucial for the function of various cells found in the tumor microenvironment, hence its critical role in tissue homeostasis. The NAD+ levels in cells are maintained by a balance between NAD+ biosynthesis and consumption, with synthesis being controlled by the Preiss-Handler, de novo, and NAD+ salvage pathways. The primary source of NAD+ synthesis in a variety of cell types is directed by the expression of the enzymes central to the three biosynthesis pathways. In this review, we describe the role of NAD+ metabolism and its synthesizing and consuming enzymes' control of cancer cell growth and immune responses in gynecologic cancers. Additionally, we review the ongoing efforts to therapeutically target the enzymes critical for NAD+ homeostasis in gynecologic cancers.

Keywords:  ADP-ribosylation; NAD+ (nicotinamide adenine dinucleotide); NAD+ homeostasis; NAD+ metabolism; gynecologic cancers; metabolic regulation; synthesis and consuming enzymes

DOI:  https://doi.org/10.3390/cancers16173085
Cancer Lett. 2024 Sep 11. pii: S0304-3835(24)00637-2. [Epub ahead of print] 217242

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.

Katerina Hlozkova, Maryna Vasylkivska, Adam Boufersaoui, Bryan Marzullo, Matus Kolarik, Natividad Alquezar-Artieda, Mehak Shaikh, Fatemeh Alaei Faradonbeh, Marketa Zaliova, Martina Zwyrtkova, Violeta Bakardijeva-Mihaylova, Meritxell Alberich-Jorda, Jan Trka, Daniel A Tennant, Julia Starkova.

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

DOI: https://doi.org/10.1016/j.canlet.2024.217242
Nat Immunol. 2024 Sep 12.

Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption.

Susan Pereira Ribeiro, Zachary Strongin, Hugo Soudeyns, Felipe Ten-Caten, Khader Ghneim, Gabriela Pacheco Sanchez, Giuliana Xavier de Medeiros, Perla Mariana Del Rio Estrada, Adam-Nicolas Pelletier, Timothy Hoang, Kevin Nguyen, Justin Harper, Sherrie Jean, Chelsea Wallace, Robert Balderas, Jeffrey D Lifson, Gopalan Raghunathan, Eric Rimmer, Cinthia Pastuskova, Guoxin Wu, Luca Micci, Ruy M Ribeiro, Chi Ngai Chan, Jacob D Estes, Guido Silvestri, Daniel M Gorman, Bonnie J Howell, Daria J Hazuda, Mirko Paiardini, Rafick P Sekaly.

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac239-infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8+ T cells in lymph nodes and reduced expression of BCL-2 in CD4+ T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4+ and CD8+ T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.

DOI: https://doi.org/10.1038/s41590-024-01952-4
Nat Aging. 2024 Sep 12.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

Jing Hou, Kai-Xuan Chen, Chen He, Xiao-Xiao Li, Mei Huang, Yang-Zi Jiang, Yu-Rui Jiao, Qiao-Ni Xiao, Wen-Zhen He, Ling Liu, Nan-Yu Zou, Min Huang, Jie Wei, Ye Xiao, Mi Yang, Xiang-Hang Luo, Chao Zeng, Guang-Hua Lei, Chang-Jun Li.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

DOI: https://doi.org/10.1038/s43587-024-00694-0
Cell Death Differ. 2024 Sep 11.

Intracellular zinc protects tumours from T cell-mediated cytotoxicity.

Emily J Lelliott, Jonathan Naddaf, Katherine Ganio, Jessica Michie, Shelly Wang, Lin Liu, Natasha Silke, Antonio Ahn, Kelly M Ramsbottom, Amelia J Brennan, Andrew J Freeman, Shom Goel, Stephin J Vervoort, Conor J Kearney, Paul A Beavis, Christopher A McDevitt, John Silke, Jane Oliaro.

Tumour immune evasion presents a significant challenge to the effectiveness of cancer immunotherapies. Recent advances in high-throughput screening techniques have uncovered that loss of antigen presentation and cytokine signalling pathways are central mechanisms by which tumours evade T cell immunity. To uncover additional vulnerabilities in tumour cells beyond the well-recognized antigen presentation pathway, we conducted a genome-wide CRISPR/Cas9 screen to identify genes that mediate resistance to chimeric-antigen receptor (CAR)-T cells, which function independently of classical antigen presentation. Our study revealed that loss of core-binding factor subunit beta (CBFβ) enhances tumour cell resistance to T cell killing, mediated through T cell-derived TNF. Mechanistically, RNA-sequencing and elemental analyses revealed that deletion of CBFβ disrupts numerous pathways including those involved in zinc homoeostasis. Moreover, we demonstrated that modulation of cellular zinc, achieved by supplementation or chelation, significantly altered tumour cell susceptibility to TNF by regulating the levels of inhibitor of apoptosis proteins. Consistent with this, treatment of tumour cells with a membrane-permeable zinc chelator had no impact on tumour cell viability alone, but significantly increased tumour cell lysis by CD8+ T cells in a TNF-dependent but perforin-independent manner. These results underscore the crucial role of intracellular zinc in regulating tumour cell susceptibility to T cell-mediated killing, revealing a novel vulnerability in tumour cells that might be exploited for the development of future cancer immunotherapeutics.

DOI: https://doi.org/10.1038/s41418-024-01369-4