bims-imseme 2023-10-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–10–15
25 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

CD8+ T cells in the cancer-immunity cycle.
STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.
Stem-like exhausted and memory CD8+ T cells in cancer.
Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.
How Nutrition Regulates Hematopoietic Stem Cell Features.
Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2 responding CD4 + T cells.
Multimodal identification of rare potent effector CD8 T cells in solid tumors.
Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism.
Apoptotic stress causes mtDNA release during senescence and drives the SASP.
Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.
Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
Immunosenescence and inflammatory markers in Cuban centenarians: implications for survival.
Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer.
Gcn4 impacts metabolic fluxes to promote yeast chronological lifespan.
Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
Metabolic reprogramming induced by DCA enhances cisplatin sensitivity through increasing mitochondrial oxidative stress in cholangiocarcinoma.
IL-2-driven CD8+ T cell phenotypes: implications for immunotherapy.
ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
Promoting The Recruitment, Engagement, And Reinvigoration of Effector T Cells via An Injectable Hydrogel with A Supramolecular Binding Capability for Cancer Immunotherapy.
Th17 Cells: Orchestrators of Mucosal Inflammation and Potential Therapeutic Targets.
Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch.
TRIM11 attenuates Treg cell differentiation by p62-selective autophagic degradation of AIM2.
Burn Patient Metabolism and Nutrition.

Immunity. 2023 Oct 10. pii: S1074-7613(23)00410-7. [Epub ahead of print]56(10): 2231-2253

CD8+ T cells in the cancer-immunity cycle.

Josephine R Giles, Anna-Maria Globig, Susan M Kaech, E John Wherry.

  CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal-metabolism-and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as "pro-drugs" that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients.

Keywords:  CD8 T cells; T cell exhaustion; cancer; immune checkpoint blockade; immunology; immunotherapy; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2023.09.005
Aging Cell. 2023 Oct 13. e13996

STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.

Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella H Kalantar, Jingting Yu, Sara SantaCruz-Calvo, Madison K Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J Drummond, Elizabeth A Proctor, Hatice Hasturk, Barbara S Nikolajczyk, Leena P Bharath.

  Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

Keywords:  CD4+ T cells; Th17 cytokines; aging; cytokines; inflammaging; mitochondria; mitochondrial STAT3; naïve CD4+ T cells

DOI:  https://doi.org/10.1111/acel.13996
Nat Rev Cancer. 2023 Oct 11.

Stem-like exhausted and memory CD8+ T cells in cancer.

Thomas Gebhardt, Simone L Park, Ian A Parish.

T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy. Here, we discuss key similarities and differences in the regulation and function of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and consider their context-specific contributions to protective immunity in diverse outcomes of cancer, including tumour escape, long-term control and eradication. Finally, we emphasize how recent advances in the understanding of the molecular regulation of stem-like exhausted T cells and memory T cells are being explored for clinical benefit in cancer immunotherapies such as checkpoint inhibition, adoptive cell therapy and vaccination.

DOI: https://doi.org/10.1038/s41568-023-00615-0
Front Immunol. 2023 ;14 1219422

Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.

Hoyul Lee, Jae-Han Jeon, Eun Soo Kim.

  Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.

Keywords:  IBD - inflammatory bowel disease; T cell; immunometabolism; inflammation; mitochondria; treatment

DOI:  https://doi.org/10.3389/fimmu.2023.1219422
Exp Hematol. 2023 Oct 08. pii: S0301-472X(23)01735-6. [Epub ahead of print]

How Nutrition Regulates Hematopoietic Stem Cell Features.

Katharina Schönberger, Nina Cabezas-Wallscheid.

  Our dietary choices significantly impact all the cells in our body. Increasing evidence suggests that diet-derived metabolites influence hematopoietic stem cell (HSC) metabolism and function, thereby actively modulating blood homeostasis. This is of particular relevance since regulating the metabolic activity of HSCs is crucial for maintaining stem cell fitness and mitigating the risk of hematological disorders. In this review, we examine the current scientific knowledge of the impact of the diet on stemness features, and we specifically highlight the established mechanisms by which dietary components modulate metabolic and transcriptional programs in adult HSCs. Gaining a deeper understanding of how nutrition influences our HSC compartment may pave the way for targeted dietary interventions with the potential to decelerate aging and improve the effectiveness of transplantation and cancer therapies.

Keywords:  Diet; Metabolism; Stem Cells (hematopoietic stem cells)

DOI:  https://doi.org/10.1016/j.exphem.2023.09.008
bioRxiv. 2023 Sep 28. pii: 2023.09.25.559429. [Epub ahead of print]

Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2 responding CD4 + T cells.

Simone Sandoval, Keegan Malany, Krista Thongphanh, Clarisa A Martinez, Michael L Goodson, Felipe Da Costa Souza, Lo-Wei Lin, Jamie Pennington, Pamela J Lein, Nancy I Kerkvliet, Allison K Ehrlich.

Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4 + T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4 + T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4 + T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4 + T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4 + T cells increases over the course of activation and proliferation in vivo . The actively dividing Nrp1 + Foxp3 - cells express the classic effector phenotype of CD44 hi CD45RB lo , and the increase in Nrp1 + Foxp3 - cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4 + T cells. The downregulation of Nrp1 on CD4 + T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4 + Foxp3 - cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo . Collectively, the data demonstrate that Nrp1 is a CD4 + T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4 + T cell responses.

DOI: https://doi.org/10.1101/2023.09.25.559429
bioRxiv. 2023 Sep 28. pii: 2023.09.26.559470. [Epub ahead of print]

Multimodal identification of rare potent effector CD8 T cells in solid tumors.

Arja Ray, Molly Bassette, Kenneth H Hu, Lomax F Pass, Bushra Samad, Alexis Combes, Vrinda Johri, Brittany Davidson, Grace Hernandez, Itzia Zaleta-Linares, Matthew F Krummel.

Antitumor immunity is driven by CD8 T cells, yet we lack signatures for the exceptional effectors in tumors, amongst the vast majority of CD8 T cells undergoing exhaustion. By leveraging the measurement of a canonical T cell activation protein (CD69) together with its RNA ( Cd69 ), we found a larger classifier for TCR stimulation-driven effector states in vitro and in vivo . This revealed exceptional 'star' effectors-highly functional cells distinguished amidst progenitor and terminally exhausted cells. Although rare in growing mouse and human tumors, they are prominent in mice during T cell-mediated tumor clearance, where they engage with tumor antigen and are superior in tumor cell killing. Employing multimodal CITE-Seq allowed de novo identification of similar rare effectors amidst T cell populations in human cancer. The identification of rare and exceptional immune states provides rational avenues for enhancement of antitumor immunity.
One sentence summary: Parsing T cell activation states using a novel reporter mouse reveals the functional identity of potent anti-tumor CD8 T cells.

DOI: https://doi.org/10.1101/2023.09.26.559470
Biochem Biophys Rep. 2023 Dec;36 101542

Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism.

Jun Ma, Qianqian Cen, Qingzhu Wang, Li Liu, Jieru Zhou.

  Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneum, and the prognosis of patients is poor. In the peritoneum of patients with EOC, TAMs (tumor associated macrophages) regulate the imbalance of T cell ratio and promote the progression and metastasis of EOC. However, the mechanism of peritoneal metastasis in EOC patients remains unclear. Here, we confirmed that the percentages of PD-L1+ TAMs in EOC tissues increased significantly, and TAMs-derived PD-L1+ exosomes affected the transcription factor PPARα to up-regulate the expression of CPT1A in CD8+ T cells, promote fatty acid oxidation, and increase reactive oxygen species to cause cell damage. The apoptosis of CD8+ T cells was increased, and the expressions of their exhaustion markers LAG3, TIM-3, and PD-1 were also up-regulated. TAMs affect T cell function through lipid metabolism, leading to peritoneal immune imbalance and promoting peritoneal metastasis of EOC. This study reveals the mechanism by which TAMs in the peritoneal microenvironment regulate T cell lipid metabolism through exosome delivery of PD-L1, and the effect of lipid metabolism on T cell function, reveals the molecular mechanism of tumor immune microenvironment affecting EOC metastasis, and further explores related pathways whether molecular blockade can be used as a means to intervene in disease progression is expected to establish a new strategy for the diagnosis and treatment of EOC.

Keywords:  CD8+ T cells; Epithelial ovarian cancer; PD-L1; Peritoneal metastasis; Tumor associated macrophages

DOI:  https://doi.org/10.1016/j.bbrep.2023.101542
Nature. 2023 Oct 11.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

DOI: https://doi.org/10.1038/s41586-023-06621-4
Cell Biosci. 2023 Oct 13. 13(1): 189

Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.

Jing Jin, Qijie Zhao, Zhigong Wei, Keliang Chen, Yonglin Su, Xiaolin Hu, Xingchen Peng.

  Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.

Keywords:  Glycolysis-Cholesterol Metabolic Axis; Immune Cells; Immunosuppressive; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s13578-023-01138-9
Aging Cell. 2023 Oct 13. e14000

Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.

Min Ji Song, Chi-Hyun Park, Haesoo Kim, Sangbum Han, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung.

  Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence-associated secretory phenotype (SASP) and stimulate chronic low-grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NF-ĸB pathways to induce SASPs. Consistently, fibroblast-specific CRAT-knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction-induced senescence.

Keywords:  carnitine acetyltransferase; cellular senescence; mitochondrial dysfunction; oxidative stress; skin aging

DOI:  https://doi.org/10.1111/acel.14000
Aging Clin Exp Res. 2023 Oct 12.

Immunosenescence and inflammatory markers in Cuban centenarians: implications for survival.

Nuris Ledón, Ana Laura Añé-Kourí, Mercedes Bárbara Ramos, Patricia Lorenzo-Luaces, Alexa Silva, Karla Pereira, Agustin Lage, Danay Saavedra.

  Centenarians are the best example of successful aging in humans. This work aimed to understand if immune status is associated with survival in Cuban centenarians. In a previous study, our group enrolled 43 centenarians and evaluated their immune status and functional capacity. 41 out of 43 recruited centenarians received follow-up phone calls, during a period of 2 years. Absolute CD4 + T cell count was higher among survivors, while the frequency of CD8 + CCR7-CD45RA + , CD8 + CD45RA + CD28-, and CD4 + CD28- T cells was higher among non-survivors. We also found that higher frequencies of terminally differentiated T cells were related to a higher risk of death, while centenarians with higher frequencies of T cells were more likely to survive. Surprisingly, neither serum inflammatory markers nor frailty/dependency was associated with survival. Our preliminary study suggests that immuno-senescence markers, but not inflammaging or functional capacity, are associated with survival beyond 100 years in a small group of Cuban centenarians.

Keywords:  CD4/CD8 ratio; Centenarians; Immunosenescence; Inflammaging; Terminally differentiated T cells

DOI:  https://doi.org/10.1007/s40520-023-02567-9
Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10

Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.

Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.

  Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.

Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics

DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
Nat Immunol. 2023 Oct 09.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu, Xi Wang, Guoliang Cui.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

DOI: https://doi.org/10.1038/s41590-023-01636-5
Front Cell Dev Biol. 2023 ;11 1266973

Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer.

Wenhui Zhang, Ren Lang.

  Succinate serves as an essential circulating metabolite within the tricarboxylic acid (TCA) cycle and functions as a substrate for succinate dehydrogenase (SDH), thereby contributing to energy production in fundamental mitochondrial metabolic pathways. Aberrant changes in succinate concentrations have been associated with pathological states, including chronic inflammation, ischemia/reperfusion (IR) injury, and cancer, resulting from the exaggerated response of specific immune cells, thereby rendering it a central area of investigation. Recent studies have elucidated the pivotal involvement of succinate and SDH in immunity beyond metabolic processes, particularly in the context of cancer. Current scientific endeavors are concentrated on comprehending the functional repercussions of metabolic modifications, specifically pertaining to succinate and SDH, in immune cells operating within a hypoxic milieu. The efficacy of targeting succinate and SDH alterations to manipulate immune cell functions in hypoxia-related diseases have been demonstrated. Consequently, a comprehensive understanding of succinate's role in metabolism and the regulation of SDH is crucial for effectively targeting succinate and SDH as therapeutic interventions to influence the progression of specific diseases. This review provides a succinct overview of the latest advancements in comprehending the emerging functions of succinate and SDH in metabolic processes. Furthermore, it explores the involvement of succinate, an intermediary of the TCA cycle, in chronic inflammation, IR injury, and cancer, with particular emphasis on the mechanisms underlying succinate accumulation. This review critically assesses the potential of modulating succinate accumulation and metabolism within the hypoxic milieu as a means to combat various diseases. It explores potential targets for therapeutic interventions by focusing on succinate metabolism and the regulation of SDH in hypoxia-related disorders.

Keywords:  cancer; immune cells; inflammation; ischemia/reperfusion (IR) injury; succinate; succinate dehydrogenase (SDH)

DOI:  https://doi.org/10.3389/fcell.2023.1266973
PLoS One. 2023 ;18(10): e0292949

Gcn4 impacts metabolic fluxes to promote yeast chronological lifespan.

Juan Facundo Gulias, Florencia Niesi, Martín Arán, Susana Correa-García, Mariana Bermúdez-Moretti.

Aging is characterized by a gradual decline in physiological integrity, which impairs functionality and increases susceptibility to mortality. Dietary restriction, mimicking nutrient scarcity without causing malnutrition, is an intervention known to decelerate the aging process. While various hypotheses have been proposed to elucidate how dietary restriction influences aging, the underlying mechanisms remain incompletely understood. This project aimed to investigate the role of the primary regulator of the general amino acid control (GAAC) pathway, the transcription factor Gcn4, in the aging process of S. cerevisiae cells. Under conditions of amino acid deprivation, which activate Gcn4, the deletion of GCN4 led to a diverse array of physiological changes in the cells. Notably, the absence of Gcn4 resulted in heightened mitochondrial activity, likely contributing to the observed increase in reactive oxygen species (ROS) accumulation. Furthermore, these mutant gcn4Δ cells exhibited reduced ethanol production despite maintaining similar glucose consumption rates, suggesting a pivotal role for Gcn4 in regulating the Crabtree effect. Additionally, there was a marked reduction in trehalose, the storage carbohydrate, within the mutant cells compared to the wild-type strain. The intracellular content of free amino acids also exhibited disparities between the wild-type and GCN4-deficient strains. Taken together, our findings indicate that the absence of GCN4 disrupts cellular homeostasis, triggering significant alterations in interconnected intracellular metabolic pathways. These disruptions have far-reaching metabolic consequences that ultimately culminate in a shortened lifespan.

DOI: https://doi.org/10.1371/journal.pone.0292949
Nat Commun. 2023 Oct 10. 14(1): 6328

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-42093-w
Front Pharmacol. 2023 ;14 1128312

Metabolic reprogramming induced by DCA enhances cisplatin sensitivity through increasing mitochondrial oxidative stress in cholangiocarcinoma.

Hanjiao Qin, Ge Zheng, Qiao Li, Luyan Shen.

  Background: Cholangiocarcinoma has obvious primary multidrug resistance and is generally resistant to cisplatin and other chemotherapy drugs and high glycolytic levels may be associated with chemotherapy resistance of cholangiocarcinoma cells. Dichloroacetate (DCA) is a specific inhibitor of PDK, which can promote mitochondrial aerobic oxidation process by activating PDH. In the past few years, there have been an increasing number of studies supporting the action of DCA against cancer, which also provided evidence for targeting metabolism to enhance the efficacy of cholangiocarcinoma chemotherapy. Methods: Glucose uptake and lactic acid secretion were used to detect cell metabolism level. Cell apoptosis and cell cycle were detected to confirm cell fate induced by cisplatin combined with DCA. Mito-TEMPO was used to inhibit mtROS to explore the relationship between oxidative stress and cell cycle arrest induced by DCA under cisplatin stress. Finally, PCR array and autophagy inhibitor CQ were used to explore the potential protective mechanism under cell stress. Results: DCA changed the metabolic model from glycolysis to aerobic oxidation in cholangiocarcinoma cells under cisplatin stress. This metabolic reprogramming increased mitochondrial reactive oxygen species (mtROS) levels, which promoted cell cycle arrest, increased the expression of antioxidant genes and activated autophagy. Inhibition of autophagy further increased the synergistic effect of DCA and cisplatin. Conclusion: DCA increased cisplatin sensitivity in cholangiocarcinoma cells via increasing the mitochondria oxidative stress and cell growth inhibition. Synergistic effects of DCA and CQ were observed in cholangiocarcinoma cells, which further increased the cisplatin sensitivity via both metabolic reprogramming and inhibition of the stress response autophagy.

Keywords:  DCA; autophagy; cholangiocarcinoma; cisplatin sensitivity; metabolic reprogramming; redox homeostasis

DOI:  https://doi.org/10.3389/fphar.2023.1128312
Trends Immunol. 2023 Oct 10. pii: S1471-4906(23)00195-3. [Epub ahead of print]

IL-2-driven CD8+ T cell phenotypes: implications for immunotherapy.

Veronika Niederlova, Oksana Tsyklauri, Marek Kovar, Ondrej Stepanek.

  The therapeutic potential of interleukin (IL)-2 in cancer treatment has been known for decades, yet its widespread adoption in clinical practice remains limited. Recently, chimeric proteins of an anti-PD-1 antibody and suboptimal IL-2 variants were shown to stimulate potent antitumor and antiviral immunity by inducing unique effector CD8+ T cells in mice. A similar subset of cytotoxic T cells is induced by depletion of regulatory T cells (Tregs), suggesting IL-2 sequestration as a major mechanism through which regulatory T cells suppress activated CD8+ T cells. Here, we present our view of how IL-2-based biologicals can boost the antitumor response at a cellular level, and propose that the role of Tregs following such treatments may have been previously overestimated.

Keywords:  IL-2; PD-1; cancer; cytotoxic T cells; immunotherapy; regulatory T cell

DOI:  https://doi.org/10.1016/j.it.2023.09.003
Cell Rep. 2023 Oct 11. pii: S2211-1247(23)01218-4. [Epub ahead of print]42(10): 113206

ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.

Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai.

  Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.

Keywords:  ApoE; CP: Metabolism; CPT1A; Glut1; fatty acid oxidation; hematopoiesis; inflammation; macrophage; microRNA-142a; microRNA-146a; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113206
Adv Mater. 2023 Oct 09. e2309667

Promoting The Recruitment, Engagement, And Reinvigoration of Effector T Cells via An Injectable Hydrogel with A Supramolecular Binding Capability for Cancer Immunotherapy.

Yueqiang Zhu, Liangjie Jin, Junbin Chen, Miao Su, Tianmeng Sun, Xianzhu Yang.

  T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant β-cyclodextrin (ALG-βCD) sites was developed and intratumorally injected to recruit CCR9+ CD8+ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9+ CD8+ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies were immobilized in the ALG-βCD hydrogel through supramolecular host-guest interactions of Ad and βCD, which facilitated engagement between CD8+ T cells and tumor cells and reinvigorated CD8+ T cells to avoid exhaustion. Base on this treatment strategy, T cell-mediated anticancer activity was promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models. This article is protected by copyright. All rights reserved.

Keywords:  T cell hitchhiking; cancer immunotherapy; engagement between T cells and tumor cells; recruiting CCR9+CD8+ T cells; reinvigoration of CD8+ T cells; supramolecular binding

DOI:  https://doi.org/10.1002/adma.202309667
Crit Rev Immunol. 2023 ;43(5): 25-52

Th17 Cells: Orchestrators of Mucosal Inflammation and Potential Therapeutic Targets.

Dorsa Iraji, Bergithe E Oftedal, Anette S B Wolff.

T helper 17 (Th17) cells represent a specialized subgroup of effector CD4+ T cells known for their role in provoking neutrophil-driven tissue inflammation, particularly within mucosal tissues. Although they are pivotal for defending the host against extracellular bacteria and fungi, they have also been associated with development of various T cell-mediated inflammatory conditions, autoimmune diseases, and even cancer. Notably, Th17 cells exhibit a dual nature, with different Th17 cell subtypes showcasing distinct effector functions and varying capacities to incite autoimmune tissue inflammation. Furthermore, Th17 cells exhibit significant plasticity, which carries important functional implications, both in terms of their expression of cytokines typically associated with other effector T cell subsets and in their interactions with regulatory CD4+ T cells. The intricate balance of Th17 cytokines can also be a double-edged sword in inflammation, autoimmunity, and cancer. Within this article, we delve into the mechanisms that govern the differentiation, function, and adaptability of Th17 cells. We culminate with an exploration of therapeutic potentials in harnessing the power of Th17 cells and their cytokines. Targeted interventions to modulate Th17 responses are emerging as promising strategies for autoimmunity, inflammation, and cancer treatment. By precisely fine-tuning Th17-related pathways, we may unlock new avenues for personalized therapeutic approaches, aiming to restore immune balance, alleviate the challenges of these disorders, and ultimately enhance the quality of life for individuals affected by them.

DOI: https://doi.org/10.1615/CritRevImmunol.2023050360
bioRxiv. 2023 Sep 27. pii: 2023.09.26.559597. [Epub ahead of print]

Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch.

Alexander S Zhovmer, Alexis Manning, Chynna Smith, Jian Wang, Xuefei Ma, Denis Tsygankov, Nikolay V Dokholyan, Alexander X Cartagena-Rivera, Rakesh K Singh, Erdem D Tabdanov.

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin's GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.
SIGNIFICANCE STATEMENT: Deciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins' GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.

DOI: https://doi.org/10.1101/2023.09.26.559597
Cell Rep. 2023 Oct 06. pii: S2211-1247(23)01243-3. [Epub ahead of print]42(10): 113231

TRIM11 attenuates Treg cell differentiation by p62-selective autophagic degradation of AIM2.

Ting Yu, Xiaofang Yang, Qiang Fu, Junyu Liang, Xinger Wu, Junli Sheng, Yitian Chen, Lu Xiao, Yuxia Wu, Dingnai Nie, Xiaolong You, Haiyan Mai, Kang Chen, Shengfeng Hu.

  Ubiquitination is an important protein modification that regulates diverse biological processes, including CD4+ T cell differentiation and functions. However, the function of most E3 ubiquitin ligases in CD4+ T cell differentiation and CD4+ T cell-mediated pathological diseases remains unclear. In this study, we find that tripartite motif-containing motif 11 (TRIM11) specifically negatively regulates regulatory T (Treg) cell differentiation in CD4+ T cells and promotes autoimmune disease development in an AIM2-dependent manner. Mechanistically, TRIM11 interacts with absent in melanoma 2 (AIM2) and promotes the selective autophagic degradation of AIM2 by inducing AIM2 ubiquitination and binding to p62 in CD4+ T cells. AIM2 attenuates AKT and FOXO1 phosphorylation, MYC signaling, and glycolysis, thereby promoting the stability of Treg cells during experimental autoimmune encephalomyelitis (EAE). Our findings suggest that TRIM11 serves as a potential target for immunotherapeutic intervention for dysregulated immune responses that lead to autoimmunity and cancers.

Keywords:  CP: Immunology; Treg cell differentiation; protein post-translational modification; selective autophagic degradation

DOI:  https://doi.org/10.1016/j.celrep.2023.113231
Phys Med Rehabil Clin N Am. 2023 Nov;pii: S1047-9651(23)00039-6. [Epub ahead of print]34(4): 717-731

Burn Patient Metabolism and Nutrition.

Johanna H Nunez, Audra T Clark.

  Following severe burns, patients have unique metabolic derangements that make adequate nutritional support imperative for their survival and recovery. Patients with burns have persistent and prolonged hypermetabolic states that lead to increased catabolism following injury. During rehabilitation, catabolism leads to increased muscle wasting and cachexia. Failure to adequately meet the patient's increased nutritional requirements can lead to poor wound healing, increased infections, and overall organ dysfunction. Because of these risks, adequate assessment and provision of nutritional needs are imperative to care for these patients.

Keywords:  Burn; Critical care; Metabolism; Nutrition

DOI:  https://doi.org/10.1016/j.pmr.2023.06.001