bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–04–14
25 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. FOXO1 is a master regulator of memory programming in CAR T cells.
  2. Decoding and Overcoming T cell Exhaustion: Epigenetic and Transcriptional Dynamics in CAR-T Cells Against Solid Tumors.
  3. CRISPR-Cas9 applications in T cells and adoptive T cell therapies.
  4. The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases.
  5. Disruption of IFNγ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells.
  6. Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma.
  7. Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells.
  8. Author Correction: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues.
  9. Correction for Sun et al., OCA-B/Pou2af1 is sufficient to promote CD4+ T cell memory and prospectively identifies memory precursors.
  10. Age-related considerations in the relationship between educational level and metabolic syndrome prevalence.
  11. Exploring the evolution of T cell function and diversity across different stages of non-small cell lung cancer.
  12. Altering β Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.
  13. Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells.
  14. Rejuvenating an old immune system.
  15. Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
  16. Driving CAR-T cells toward solid lung tumors.
  17. T cell cascade regulation initiates systemic antitumor immunity through living drug factory of anti-PD-1/IL-12 engineered probiotics.
  18. MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.
  19. Immunoregulatory natural killer cells.
  20. Fructose overconsumption-induced reprogramming of microglia metabolism and function.
  21. Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients.
  22. Toosendanin inhibits T-cell proliferation through the P38 MAPK signalling pathway.
  23. Aging Gut Microbiome in Healthy and Unhealthy Aging.
  24. Research Progress in Skin Aging and Immunity.
  25. Telomeres and aging: on and off the planet!
  1. Nature. 2024 Apr 10.
    FOXO1 is a master regulator of memory programming in CAR T cells.
    Alexander E Doan, Katherine P Mueller, Andy Y Chen, Geoffrey T Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A Grupp, Susan E McClory, Caleb A Lareau, Joseph A Fraietta, Elena Sotillo, Ansuman T Satpathy, Crystal L Mackall, Evan W Weber.
      A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.
    DOI:  https://doi.org/10.1038/s41586-024-07300-8
  2. Mol Ther. 2024 Apr 05. pii: S1525-0016(24)00220-X. [Epub ahead of print]
    Decoding and Overcoming T cell Exhaustion: Epigenetic and Transcriptional Dynamics in CAR-T Cells Against Solid Tumors.
    Taeyoung Ahn, Eun-Ah Bae, Hyungseok Seo.
      T cell exhaustion, which is observed in various chronic infections and malignancies, is characterized by elevated expression of multiple inhibitory receptors, impaired effector functions, decreased proliferation, and reduced cytokine production. Notably, while adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T therapy, have shown promise in treating cancer and other diseases, the efficacy of these therapies is often compromised by T cell exhaustion. It is imperative, therefore, to understand the mechanisms underlying this exhaustion to promote advances in T cell-related therapies. Here, we divided exhausted T cells into three distinct subsets according to their developmental and functional profiles: stem-like progenitor cells (TexProg), intermediately exhausted cells (Texint), and terminally exhausted cells (Texterm). These subsets are carefully regulated by synergistic mechanisms that involve transcriptional and epigenetic modulators. Key transcription factors, such as TCF1, BACH2, and TOX, are crucial for defining and sustaining exhaustion phenotypes. Concurrently, epigenetic regulators, such as TET2 and DNMT3A, shape the chromatin dynamics that direct T cell fate. The interplay of these molecular drivers has recently been highlighted in CAR-T research, revealing promising therapeutic directions. Thus, a profound understanding of exhausted T cell hierarchies and their molecular complexities may reveal innovative and improved tumor treatment strategies.
    Keywords:  CAR-T; Epigenetic enzymes; T cell exhaustion; Transcription factors
    DOI:  https://doi.org/10.1016/j.ymthe.2024.04.004
  3. Cell Mol Biol Lett. 2024 Apr 12. 29(1): 52
    CRISPR-Cas9 applications in T cells and adoptive T cell therapies.
    Xiaoying Chen, Shuhan Zhong, Yonghao Zhan, Xuepei Zhang.
      T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats-associated protein 9 (CRISPR-Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR-Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR-Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR-Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.
    Keywords:  Adoptive T cell therapy; CAR-T; CRISPR–Cas9; T cells; TCR-T; TIL
    DOI:  https://doi.org/10.1186/s11658-024-00561-1
  4. J Mol Med (Berl). 2024 Apr 11.
    The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases.
    Antero Salminen.
      The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. KEY MESSAGES: Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.
    Keywords:  Aging; Immune tolerance; Immunosuppression; Inflammaging; Inflammation
    DOI:  https://doi.org/10.1007/s00109-024-02444-6
  5. J Immunol. 2024 Apr 12. pii: ji2300388. [Epub ahead of print]
    Disruption of IFNγ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells.
    Chakrapani Vemulawada, Pranav S Renavikar, Michael P Crawford, Scott Steward-Tharp, Nitin J Karandikar.
      An imbalance between proinflammatory and regulatory processes underlies autoimmune disease pathogenesis. We have shown that acute relapses of multiple sclerosis are characterized by a deficit in the immune suppressive ability of CD8+ T cells. These cells play an important immune regulatory role, mediated in part through cytotoxicity (perforin [PRF]/granzyme [GZM]) and IFNγ secretion. In this study, we further investigated the importance of IFNγ-, GZMB-, PRF1-, and LYST-associated pathways in CD8+ T cell-mediated suppression. Using the CRISPR-Cas9 ribonucleoprotein transfection system, we first optimized efficient gene knockout while maintaining high viability in primary bulk human CD8+ T cells. Knockout was confirmed through quantitative real-time PCR assays in all cases, combined with flow cytometry where appropriate, as well as confirmation of insertions and/or deletions at genomic target sites. We observed that the knockout of IFNγ, GZMB, PRF1, or LYST, but not the knockout of IL4 or IL5, resulted in significantly diminished in vitro suppressive ability in these cells. Collectively, these results reveal a pivotal role for these pathways in CD8+ T cell-mediated immune suppression and provide important insights into the biology of human CD8+ T cell-mediated suppression that could be targeted for immunotherapeutic intervention.
    DOI:  https://doi.org/10.4049/jimmunol.2300388
  6. Cancer Sci. 2024 Apr 09.
    Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma.
    Yao Wang, Lin Ma, Yu Chen, Wenhua Yun, Jinming Yu, Xiangjiao Meng.
      Recent studies have highlighted the pivotal roles of T cell transcription factors TCF-1 and TOX in modulating the immune response in cancer, with TCF-1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor-draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem-like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease-free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.
    Keywords:  LUAD; TCF1; prognosis; tumor microenvironment; tumor‐draining lymph nodes
    DOI:  https://doi.org/10.1111/cas.16177
  7. Nat Commun. 2024 Apr 12. 15(1): 3173
    Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells.
    Mike B Barnkob, Yale S Michaels, Violaine André, Philip S Macklin, Uzi Gileadi, Salvatore Valvo, Margarida Rei, Corinna Kulicke, Ji-Li Chen, Vitul Jain, Victoria K Woodcock, Huw Colin-York, Andreas V Hadjinicolaou, Youxin Kong, Viveka Mayya, Julie M Mazet, Gracie-Jennah Mead, Joshua A Bull, Pramila Rijal, Christopher W Pugh, Alain R Townsend, Audrey Gérard, Lars R Olsen, Marco Fritzsche, Tudor A Fulga, Michael L Dustin, E Yvonne Jones, Vincenzo Cerundolo.
      Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.
    DOI:  https://doi.org/10.1038/s41467-024-47424-z
  8. Nat Cancer. 2024 Apr 11.
    Author Correction: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues.
    Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W Katona, Terence P F Gade, Don L Siegel, Jörg Schrader, David C Metz, Carl H June, Xianxin Hua.
      
    DOI:  https://doi.org/10.1038/s43018-024-00766-5
  9. Proc Natl Acad Sci U S A. 2024 Apr 16. 121(16): e2405830121
    Correction for Sun et al., OCA-B/Pou2af1 is sufficient to promote CD4+ T cell memory and prospectively identifies memory precursors.
      
    DOI:  https://doi.org/10.1073/pnas.2405830121
  10. J Cardiovasc Thorac Res. 2024 ;16(1): 64
    Age-related considerations in the relationship between educational level and metabolic syndrome prevalence.
    Fatemeh Omidi.
      
    DOI:  https://doi.org/10.34172/jcvtr.33084
  11. Am J Cancer Res. 2024 ;14(3): 1243-1257
    Exploring the evolution of T cell function and diversity across different stages of non-small cell lung cancer.
    Cheng-Yu Chang, Shih-Chieh Chang, Yu-Feng Wei, Yu-Ting Tseng, Chien-Hong Chou, Ying-Yin Chen, Chung-Yu Chen, Yi-Ling Ye.
      The immune system plays a key role in detecting and fighting cancerous tumors. T cells are a crucial component in both natural and therapeutic cancer immunoediting responses, but it is unclear if they are the primary agents of these processes. In this study, patients with lung lesions detected by CT scan were selected, and their peripheral blood samples were analyzed for T cell population and serum cytokines/chemokines. T cell subtypes (CD3, CD4, CD8, CD27, CD28, CD45, CD45RA, CD57, CCR7, and PD1) and serum cytokines/chemokines (IL-2, IL-6, IL-10, IFN-γ, TGF-β, TNFα, CXCL1, CXCL9, and CXCL12) were measured by flow cytometry and analysis before surgical resection or other cancer treatments. The frequency of T cell subpopulations in patients with lung cancer (n = 111) corresponded to those seen in patients with T cell exhaustion. As lung cancer progressed, the proportion of effector memory T cells decreased, while the proportion of naive T cells, PD-1, CD57+, CD28+CD27+, CD45RA+, and CD3+CD4+CCR7 increased. Circulating CD8+PD1+ T cells were positively correlated with intra-tumoral PD-L1 expression. Concurrently, serum levels of IL-2, TGF-β, and CXCL9 decreased, while IL-6, IL-10, IFN-γ, and CXCL12 increased during the progression of lung cancer. In conclusion, T cell dysfunction is associated with cancer progression, particularly in advanced-stage lung cancer, and cancer immunoediting will provide early-stage cancer detection and further therapeutic strategies.
    Keywords:  T cell exhaustion; T cell immunity; immunoediting; immunosurveillance; lung cancer
    DOI:  https://doi.org/10.62347/ARYH6451
  12. J Immunol. 2024 Apr 08. pii: ji2300785. [Epub ahead of print]
    Altering β Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.
    David J De George, Gaurang Jhala, Claudia Selck, Prerak Trivedi, Thomas C Brodnicki, Leanne Mackin, Thomas W Kay, Helen E Thomas, Balasubramanian Krishnamurthy.
      Chronic destruction of insulin-producing pancreatic β cells by T cells results in autoimmune diabetes. Similar to other chronic T cell-mediated pathologies, a role for T cell exhaustion has been identified in diabetes in humans and NOD mice. The development and differentiation of exhausted T cells depends on exposure to Ag. In this study, we manipulated β cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the β cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated β cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 mice with IGRP expression induced in APCs, IGRP-reactive T cells remained exposed to high levels of IGRP in the islets and periphery. Consequently, functionally exhausted TEX cells, with reduced granzyme B expression, were significantly increased in these mice and this correlated with diabetes protection. These results indicate that intermediate Ag exposure in wild-type NOD8.3 islets allows T cells to enter the exhaustion program without becoming functionally exhausted. Moreover, Ag exposure can be manipulated to target this key cytotoxic population either by limiting the generation of cytotoxic TIM3+ cells or by driving their functional exhaustion, with both resulting in diabetes protection.
    DOI:  https://doi.org/10.4049/jimmunol.2300785
  13. Front Immunol. 2024 ;15 1366096
    Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells.
    Han Zhang, Pengpeng Zhang, Xuefeng Lin, Lin Tan, Yuhang Wang, Xiaoteng Jia, Kai Wang, Xin Li, Daqiang Sun.
       Background: The tumor microenvironment (TME) plays a pivotal role in the progression and metastasis of lung adenocarcinoma (LUAD). However, the detailed characteristics of LUAD and its associated microenvironment are yet to be extensively explored. This study aims to delineate a comprehensive profile of the immune cells within the LUAD microenvironment, including CD8+ T cells, CD4+ T cells, and myeloid cells. Subsequently, based on marker genes of exhausted CD8+ T cells, we aim to establish a prognostic model for LUAD.
    Method: Utilizing the Seurat and Scanpy packages, we successfully constructed an immune microenvironment atlas for LUAD. The Monocle3 and PAGA algorithms were employed for pseudotime analysis, pySCENIC for transcription factor analysis, and CellChat for analyzing intercellular communication. Following this, a prognostic model for LUAD was developed, based on the marker genes of exhausted CD8+ T cells, enabling effective risk stratification in LUAD patients. Our study included a thorough analysis to identify differences in TME, mutation landscape, and enrichment across varying risk groups. Moreover, by integrating risk scores with clinical features, we developed a new nomogram. The expression of model genes was validated via RT-PCR, and a series of cellular experiments were conducted, elucidating the potential oncogenic mechanisms of GALNT2.
    Results: Our study developed a single-cell atlas for LUAD from scRNA-seq data of 19 patients, examining crucial immune cells in LUAD's microenvironment. We underscored pDCs' role in antigen processing and established a Cox regression model based on CD8_Tex-LAYN genes for risk assessment. Additionally, we contrasted prognosis and tumor environments across risk groups, constructed a new nomogram integrating clinical features, validated the expression of model genes via RT-PCR, and confirmed GALNT2's function in LUAD through cellular experiments, thereby enhancing our understanding and approach to LUAD treatment.
    Conclusion: The creation of a LUAD single-cell atlas in our study offered new insights into its tumor microenvironment and immune cell interactions, highlighting the importance of key genes associated with exhausted CD8+ T cells. These discoveries have enabled the development of an effective prognostic model for LUAD and identified GALNT2 as a potential therapeutic target, significantly contributing to the improvement of LUAD diagnosis and treatment strategies.
    Keywords:  CD4+ T cells; CD8+ T cells; GALNT2; LUAD; myeloid; pDCs
    DOI:  https://doi.org/10.3389/fimmu.2024.1366096
  14. Nat Rev Immunol. 2024 Apr 09.
    Rejuvenating an old immune system.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01031-7
  15. Sci Adv. 2024 Apr 12. 10(15): eadl0372
    Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
    Yu Zhuang, Shengjie Jiang, Xiaoling Deng, An Lao, Xiaolin Hua, Yun Xie, Lingyong Jiang, Xudong Wang, Kaili Lin.
      Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.
    DOI:  https://doi.org/10.1126/sciadv.adl0372
  16. Mol Ther Oncol. 2024 Mar 21. 32(1): 200764
    Driving CAR-T cells toward solid lung tumors.
    Frank J T Staal, Federico Avila-Moreno.
      
    DOI:  https://doi.org/10.1016/j.omton.2024.200764
  17. Cell Rep. 2024 Apr 09. pii: S2211-1247(24)00414-5. [Epub ahead of print]43(4): 114086
    T cell cascade regulation initiates systemic antitumor immunity through living drug factory of anti-PD-1/IL-12 engineered probiotics.
    Jianhong Liao, Hong Pan, Guojun Huang, Han Gong, Ze Chen, Ting Yin, Baozhen Zhang, Tingtao Chen, Mingbin Zheng, Lintao Cai.
      Immune checkpoint blockade (ICB) has revolutionized cancer therapy but only works in a subset of patients due to the insufficient infiltration, persistent exhaustion, and inactivation of T cells within a tumor. Herein, we develop an engineered probiotic (interleukin [IL]-12 nanoparticle Escherichia coli Nissle 1917 [INP-EcN]) acting as a living drug factory to biosynthesize anti-PD-1 and release IL-12 for initiating systemic antitumor immunity through T cell cascade regulation. Mechanistically, INP-EcN not only continuously biosynthesizes anti-PD-1 for relieving immunosuppression but also effectively cascade promote T cell activation, proliferation, and infiltration via responsive release of IL-12, thus reaching a sufficient activation threshold to ICB. Tumor targeting and colonization of INP-EcNs dramatically increase local drug accumulations, significantly inhibiting tumor growth and metastasis compared to commercial inhibitors. Furthermore, immune profiling reveals that anti-PD-1/IL-12 efficiently cascade promote antitumor effects in a CD8+ T cell-dependent manner, clarifying the immune interaction of ICB and cytokine activation. Ultimately, such engineered probiotics achieve a potential paradigm shift from T cell exhaustion to activation and show considerable promise for antitumor bio-immunotherapy.
    Keywords:  CP: Cancer; anti-PD-1; engineered probiotics; immune cascade regulation; interleukin-12; living drug factory
    DOI:  https://doi.org/10.1016/j.celrep.2024.114086
  18. bioRxiv. 2024 Mar 29. pii: 2024.03.25.586170. [Epub ahead of print]
    MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.
    Samantha N Hart, Raji Lenin, Jamie Sturgill, Philip A Kern, Barbara Nikolajczyk.
      Metabolism research is increasingly recognizing the contributions of organelle crosstalk to metabolic regulation. Mitochondria-associated membranes (MAMs), which are structures connecting the mitochondria and endoplasmic reticulum (ER), are critical in a myriad of cellular functions linked to cellular metabolism. MAMs control calcium signaling, mitochondrial transport, redox balance, protein folding/degradation, and in some studies, metabolic health. The possibility that MAMs drive changes in cellular function in individuals with Type 2 Diabetes (T2D) is controversial. Although disruptions in MAMs that change the distance between the mitochondria and ER, MAM protein composition, or disrupt downstream signaling, can perpetuate inflammation, one key trait of T2D. However, the full scope of this structure's role in immune cell health and thus T2D-associated inflammation remains unknown. We show that human immune cell MAM proteins and their associated functions are not altered by T2D and thus unlikely to contribute to metaflammation.
    DOI:  https://doi.org/10.1101/2024.03.25.586170
  19. Clin Chim Acta. 2024 Apr 05. pii: S0009-8981(24)00137-2. [Epub ahead of print] 117896
    Immunoregulatory natural killer cells.
    Kevin Roe.
      This review discusses a broader scope of functional roles for NK cells. Despite the well-known cytolytic and inflammatory roles of NK cells against tumors and pathogenic diseases, extensive evidence demonstrates certain subsets of NK cells have defacto immunoregulatory effects and have a role in inducing anergy or lysis of antigen-activated T cells and regulating several autoimmune diseases. Furthermore, recent evidence suggests certain subsets of immunoregulatory NK cells can cause anergy or lysis of antigen-activated T cells to regulate hyperinflammatory diseases, including multisystem inflammatory syndrome. Several pathogens induce T cell and NK cell exhaustion and/or suppression, which impair the immune system's control of the replication speed of virulent pathogens and tumors and result in extensive antigens and antigen-antibody immune complexes, potentially inducing a Type III hypersensitivity immune reaction. The Type III hypersensitivity immune reaction induces immune cell secretion of proteinases, which can create autoantigens which activate T cells to initiate autoimmune and/or hyperinflammatory diseases. Furthermore, pathogen induced NK cell exhaustion and/or suppression will inhibit NK cells which would have induced the anergy or lysis of activated T cells to regulate autoimmune and hyperinflammatory diseases. Autoimmune and hyperinflammatory diseases can be consequences of the dual lymphocyte exhaustion and/or suppression effects during infections, by creating autoimmune and/or hyperinflammatory diseases, while also impairing lymphocytes which would have regulated these diseases.
    Keywords:  Autoimmune diseases; Hyperinflammatory diseases; MIS; Multisystem inflammatory syndrome; NK cells; T cells
    DOI:  https://doi.org/10.1016/j.cca.2024.117896
  20. Front Immunol. 2024 ;15 1375453
    Fructose overconsumption-induced reprogramming of microglia metabolism and function.
    Kenneth K Y Ting.
      The overconsumption of dietary fructose has been proposed as a major culprit for the rise of many metabolic diseases in recent years, yet the relationship between a high fructose diet and neurological dysfunction remains to be explored. Although fructose metabolism mainly takes place in the liver and intestine, recent studies have shown that a hyperglycemic condition could induce fructose metabolism in the brain. Notably, microglia, which are tissue-resident macrophages (Mφs) that confer innate immunity in the brain, also express fructose transporters (GLUT5) and are capable of utilizing fructose as a carbon fuel. Together, these studies suggest the possibility that a high fructose diet can regulate the activation and inflammatory response of microglia by metabolic reprogramming, thereby altering the susceptibility of developing neurological dysfunction. In this review, the recent advances in the understanding of microglia metabolism and how it supports its functions will be summarized. The results from both in vivo and in vitro studies that have investigated the mechanistic link between fructose-induced metabolic reprogramming of microglia and its function will then be reviewed. Finally, areas of controversies and their associated implications, as well as directions that warrant future research will be highlighted.
    Keywords:  GLUT5; fructose metabolism; glycolytic reprogramming; immunometabolism; inflammation; macrophages; microglia; neurological dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2024.1375453
  21. Front Immunol. 2024 ;15 1348189
    Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients.
    Abdullah Al-Danakh, Mohammed Safi, Yuli Jian, Linlin Yang, Xinqing Zhu, Qiwei Chen, Kangkang Yang, Shujing Wang, Jianjun Zhang, Deyong Yang.
      Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer.
    Keywords:  aging; immune biomarkers; immune checkpoint inhibitors; immunosenescence; neoplasm
    DOI:  https://doi.org/10.3389/fimmu.2024.1348189
  22. Eur J Pharmacol. 2024 Apr 06. pii: S0014-2999(24)00250-4. [Epub ahead of print] 176562
    Toosendanin inhibits T-cell proliferation through the P38 MAPK signalling pathway.
    Ting Zhang, Xing-Yan Luo, Lin Jing, Chunfen Mo, Huijie Guo, Shuxia Yang, Yantang Wang, Ketian Zhao, Yi Lai, Yang Liu.
      In recent years, immunosuppressants have shown significant success in the treatment of autoimmune diseases. Therefore, there is an urgent need to develop additional immunosuppressants that offer more options for patients. Toosendanin has been shown to have immunosuppressive activity in vitro as well as effects on autoimmune hepatitis (AIH) in vivo. Toosendanin did not induce apoptosis in activated T-cells but did affect the survival rate of naive T-cells. Toosendanin did not affect the expression of CD25 or secretion of IL-2 by activated T-cells, and not affect the expression of IL-4 and INF-γ. Toosendanin did not affect the phosphorylation of STAT5, ERK, AKT, P70S6K. However, toosendanin inhibited proliferation of anti-CD3/anti-CD28 mAbs-activated T-cells with IC50 of (10 ± 2.02) nM. Toosendanin arrested the cell cycle in the G0/G1 phase, significantly inhibited IL-6 and IL-17A secretion, promoted IL-10 expression, and inhibited the P38 MAPK pathway. Finally, toosendanin significantly alleviated ConA-induced AIH in mice. In Summary, toosendanin exhibited immunosuppressive activity in vivo and in vitro. Toosendanin inhibits the proliferation of activated T-cells through the P38 MAPK signalling pathway, significantly suppresses the expression of inflammatory factors, enhances the expression of anti-inflammatory factors, and effectively alleviates ConA-induced AIH in mice, suggesting that toosendanin may be a lead compound for the development of novel immunomodulatory agents with improved efficacy and reduced toxicity.
    Keywords:  Autoimmune disease; Autoimmune hepatitis; Immunosuppressant; P38 MAPK; Toosendanin
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176562
  23. Aging Dis. 2024 Apr 09.
    Aging Gut Microbiome in Healthy and Unhealthy Aging.
    Yangyanqiu Wang, Zhanbo Qu, Jian Chu, Shuwen Hun.
      The characteristics of human aging manifest in tissue and organ function decline, heightening susceptibility to age-related ailments, thereby presenting novel challenges to fostering and sustaining healthy longevity. In recent years, an abundance of research on human aging has surfaced. Intriguingly, evidence suggests a pervasive correlation among gut microbiota, bodily functions, and chronic diseases. From infancy to later stages of adulthood, healthy individuals witness dynamic shifts in gut microbiota composition. This microbial community is associated with tissue and organ function deterioration (e.g., brain, bones, muscles, immune system, vascular system) and heightened risk of age-related diseases. Thus, we present a narrative review of the aging gut microbiome in both healthy and unhealthy aging contexts. Additionally, we explore the potential for adjustments to physical health based on gut microbiome analysis and how targeting the gut microbiome can potentially slow down the aging process.
    DOI:  https://doi.org/10.14336/AD.2024.0331
  24. Int J Mol Sci. 2024 Apr 07. pii: 4101. [Epub ahead of print]25(7):
    Research Progress in Skin Aging and Immunity.
    Xin He, Xinyu Gao, Weidong Xie.
      Skin aging is a complex process involving structural and functional changes and is characterized by a decrease in collagen content, reduced skin thickness, dryness, and the formation of wrinkles. This process is underpinned by multiple mechanisms including the free radical theory, inflammation theory, photoaging theory, and metabolic theory. The skin immune system, an indispensable part of the body's defense mechanism, comprises macrophages, lymphocytes, dendritic cells, and mast cells. These cells play a pivotal role in maintaining skin homeostasis and responding to injury or infection. As age advances, along with various internal and external environmental stimuli, skin immune cells may undergo senescence or accelerated aging, characterized by reduced cell division capability, increased mortality, changes in gene expression patterns and signaling pathways, and altered immune cell functions. These changes collectively impact the overall function of the immune system. This review summarizes the relationship between skin aging and immunity and explores the characteristics of skin aging, the composition and function of the skin immune system, the aging of immune cells, and the effects of these cells on immune function and skin aging. Immune dysfunction plays a significant role in skin aging, suggesting that immunoregulation may become one of the important strategies for the prevention and treatment of skin aging.
    Keywords:  immune cells; immune function; inflammatory response; skin aging
    DOI:  https://doi.org/10.3390/ijms25074101
  25. Biogerontology. 2024 Apr;25(2): 313-327
    Telomeres and aging: on and off the planet!
    Christopher E Mason, Maria A Sierra, Henry J Feng, Susan M Bailey.
      Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.
    Keywords:  Aging; Mitochondrial dysregulation; Omics; Oxidative stress; Radiation; Space; Telomeres
    DOI:  https://doi.org/10.1007/s10522-024-10098-7
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