bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–04–04
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.
  2. Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)-T Cells.
  3. Memory T-Cell Heterogeneity and Terminology.
  4. ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses.
  5. m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
  6. How to Reliably Define Human CD8+ T-Cell Subsets: Markers Playing Tricks.
  7. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy.
  8. Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade.
  9. Cell Death and Inflammation: The Role of Mitochondria in Health and Disease.
  10. Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells.
  11. Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis.
  12. The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing.
  13. Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.
  14. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.
  15. The Complex Integration of T-cell Metabolism and Immunotherapy.
  16. The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation.
  17. Reversal of exhaustion in engineered T cells.
  1. Nat Commun. 2021 Mar 31. 12(1): 1980
    Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.
    Norzawani Buang, Lunnathaya Tapeng, Victor Gray, Alessandro Sardini, Chad Whilding, Liz Lightstone, Thomas D Cairns, Matthew C Pickering, Jacques Behmoaras, Guang Sheng Ling, Marina Botto.
      The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.
    DOI:  https://doi.org/10.1038/s41467-021-22312-y
  2. Cancers (Basel). 2021 Mar 11. pii: 1229. [Epub ahead of print]13(6):
    Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)-T Cells.
    Ali Hosseini Rad S M, Joshua Colin Halpin, Mojtaba Mollaei, Samuel W J Smith Bell, Nattiya Hirankarn, Alexander D McLellan.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.
    Keywords:  CAR T cell therapy; T cell metabolism; memory T cell; metabolic reprogramming; mitochondria
    DOI:  https://doi.org/10.3390/cancers13061229
  3. Cold Spring Harb Perspect Biol. 2021 Mar 29. pii: a037929. [Epub ahead of print]
    Memory T-Cell Heterogeneity and Terminology.
    Yuki Muroyama, E John Wherry.
      Immunological memory and exhaustion are fundamental features of adaptive immunity. Recent advances reveal increasing heterogeneity and diversity among CD8 T-cell subsets, resulting in new subsets to annotate and understand. Here, we review our current knowledge of differentiation and maintenance of memory and exhausted CD8 T cells, including phenotypic classification, developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors. Additionally, we use this outline to discuss the nomenclature of effector, memory, and exhausted CD8 T cells. Finally, we discuss how new findings about these cell types may impact the therapeutic efficacy and development of immunotherapies targeting effector, memory, and/or exhausted CD8 T cells in chronic infections and cancer.
    DOI:  https://doi.org/10.1101/cshperspect.a037929
  4. Exp Mol Med. 2021 Apr 01.
    ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses.
    Jung-Ah Kang, Ji-Sun Kwak, Sang-Heon Park, Kyu-Young Sim, Seul Ki Kim, Youngnim Shin, In Jung Jung, Jeong-In Yang, Jang-Soo Chun, Sung-Gyoo Park.
      Zinc is a trace element that is essential for immune responses. Therefore, changes in cellular zinc levels in specific immune cells may influence inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). However, the regulation of zinc mobilization in immune cells and its role in the pathogenesis of RA are not fully understood. Thus, we investigated the roles of zinc transporters in RA pathogenesis. We demonstrated that ZIP8 was specifically upregulated in CD4+ T cells that infiltrated the inflamed joint and that ZIP8 deficiency in CD4+ T cells abrogated collagen-induced arthritis. ZIP8 deficiency dramatically affected zinc influx in effector T cells and profoundly reduced T cell receptor (TCR)-mediated signaling, including NF-κB and MAPK signaling, which are pathways that are involved in T helper (Th) 17 cell differentiation. Taken together, our findings suggest that ZIP8 depletion in CD4+ T cells attenuates TCR signaling due to insufficient cellular zinc, thereby reducing the function of effector CD4+ T cells, including Th17 cells. Our results also suggest that targeting ZIP8 may be a useful strategy to inhibit RA development and pathogenesis.
    DOI:  https://doi.org/10.1038/s12276-021-00591-1
  5. Nat Cell Biol. 2021 Apr 01.
    m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
    Pingyu Liu, Fuming Li, Jianhuang Lin, Takeshi Fukumoto, Timothy Nacarelli, Xue Hao, Andrew V Kossenkov, M Celeste Simon, Rugang Zhang.
      Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.
    DOI:  https://doi.org/10.1038/s41556-021-00656-3
  6. Cold Spring Harb Perspect Biol. 2021 Mar 29. pii: a037747. [Epub ahead of print]
    How to Reliably Define Human CD8+ T-Cell Subsets: Markers Playing Tricks.
    Michiel C van Aalderen, Rene A W van Lier, Pleun Hombrink.
      In recent years, our understanding about the functional complexity of CD8+ T-cell populations has increased tremendously. The immunology field is now facing challenges to translate these insights into phenotypic definitions that correlate reliably with distinct functional traits. This is key to adequately monitor and understand compound immune responses including vaccination and immunotherapy regimens. Here we will summarize our understanding of the current state in the human CD8+ T-cell subset characterization field. We will address how reliably the currently used cell surface markers are connected to differentiation status and function of particular subsets. By restricting ourselves to CD8+ αβ T cells, we will focus mostly on major histocompatibility complex (MHC) class I-restricted virus- and tumor-specific T cells. This comes with a major advantage as fluorescently labeled peptide-loaded MHC class I multimers have been widely used to identify and characterize these cells.
    DOI:  https://doi.org/10.1101/cshperspect.a037747
  7. Sci Transl Med. 2021 Mar 31. pii: eaaz6314. [Epub ahead of print]13(587):
    Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy.
    Xia Liu, Celine L Hartman, Lingyun Li, Carolyn J Albert, Fusheng Si, Aiqin Gao, Lan Huang, Yangjing Zhao, Wenli Lin, Eddy C Hsueh, Lizong Shen, Qixiang Shao, Daniel F Hoft, David A Ford, Guangyong Peng.
      The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.
    DOI:  https://doi.org/10.1126/scitranslmed.aaz6314
  8. Blood Adv. 2021 Apr 13. 5(7): 1816-1829
    Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade.
    Mikaël Roussel, Kieu-Suong Le, Clémence Granier, Francisco Llamas Gutierrez, Etienne Foucher, Simon Le Gallou, Céline Pangault, Luc Xerri, Vincent Launay, Thierry Lamy, Eric Tartour, Daniel Olive, Thierry Fest.
      In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell-like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003080
  9. Cells. 2021 Mar 03. pii: 537. [Epub ahead of print]10(3):
    Cell Death and Inflammation: The Role of Mitochondria in Health and Disease.
    Anna Picca, Riccardo Calvani, Hélio José Coelho-Junior, Emanuele Marzetti.
      Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell's fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy-apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity.
    Keywords:  apoptosis; damage-associated molecular patterns (DAMPs); immunogenic cell death; innate immunity; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control (MQC); mitophagy; oxidative stress; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/cells10030537
  10. Biomedicines. 2021 Mar 01. pii: 246. [Epub ahead of print]9(3):
    Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells.
    Dirk Reinhold, Karina Guttek, Annika Reddig, Linda Voss, Claudia Schubert, Sascha Kahlfuss, Kurt Grüngreiff, Burkhart Schraven, Annegret Reinhold.
      T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells. To understand the suppressive effect of zinc on T cell function, we here investigated the influence of zinc aspartate on human T cells focusing on the secretion of immunosuppressive cytokines, induction of apoptosis, and caspase 3/7 activity. To this end, we monitored either freshly stimulated or pre-activated human T cells in the presence of zinc aspartate from 40-140 µM over a period of 72 h. Under both experimental conditions, we observed a dose-dependent suppression of human T cell proliferation. While IL-1ra, latent TGF-β1, and IL-10 were dose-dependently reduced, we, unexpectedly, detected elevated levels of IL-16 upon zinc supplementation. In addition, the number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis, steadily increased at zinc aspartate concentrations exceeding 100 µM. Taken together, our findings suggest that zinc aspartate impairs T cell fitness and might be beneficial for the treatment of T cell-mediated autoimmune diseases.
    Keywords:  IL-16; T cells; apoptosis; cytokine; proliferation; zinc
    DOI:  https://doi.org/10.3390/biomedicines9030246
  11. Infect Immun. 2021 Mar 29. pii: IAI.00768-20. [Epub ahead of print]
    Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis.
    Woojong Lee, Autumn Larsen, Brock Kingstad-Bakke, Chandranaik B Marinaik, M Suresh.
      Development of T-cell-based subunit protein vaccines against diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Here, we have identified a nano-emulsion adjuvant Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes (LM) We further evaluated whether cross-presentation induced by ADJ, can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to LM Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and up-regulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to LM, a model intracellular pathogen.
    DOI:  https://doi.org/10.1128/IAI.00768-20
  12. Int J Mol Sci. 2021 Mar 06. pii: 2668. [Epub ahead of print]22(5):
    The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing.
    Yu-Jih Su, Pei-Wen Wang, Shao-Wen Weng.
      During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.
    Keywords:  ageing; inflammation; mitochondria; regeneration
    DOI:  https://doi.org/10.3390/ijms22052668
  13. Clin Transl Med. 2021 Mar;11(3): e372
    Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.
    Premranjan Kumar, Chun Liu, Jean W Hsu, Shaji Chacko, Charles Minard, Farook Jahoor, Rajagopal V Sekhar.
       BACKGROUND: Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition.
    METHODS: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition.
    RESULTS: GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.
    CONCLUSIONS: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.
    Keywords:  aging; cognition; inflammation; insulin resistance; mitochondria; oxidative stress; strength
    DOI:  https://doi.org/10.1002/ctm2.372
  14. Nat Commun. 2021 Mar 30. 12(1): 1971
    Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.
    Kiran Todkar, Lilia Chikhi, Véronique Desjardins, Firas El-Mortada, Geneviève Pépin, Marc Germain.
      Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson's disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.
    DOI:  https://doi.org/10.1038/s41467-021-21984-w
  15. Cancer Discov. 2021 Apr 01.
    The Complex Integration of T-cell Metabolism and Immunotherapy.
    Matthew Z Madden, Jeffrey C Rathmell.
      Immune oncology approaches of adoptive cell therapy and immune checkpoint blockade aim to activate T cells to eliminate tumors. Normal stimulation of resting T cells induces metabolic reprogramming from catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and back to oxidative metabolism in long-lived memory cells. These metabolic reprogramming events are now appreciated to be essential aspects of T-cell function and fate. Here, we review these transitions, how they are disrupted by T-cell interactions with tumors and the tumor microenvironment, and how they can inform immune oncology to enhance T-cell function against tumors. SIGNIFICANCE: T-cell metabolism plays a central role in T-cell fate yet is altered in cancer in ways that can suppress antitumor immunity. Here, we discuss challenges and opportunities to stimulate effector T-cell metabolism and improve cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0569
  16. Nat Commun. 2021 03 29. 12(1): 1940
    The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation.
    Man Shang, Huijie Yang, Ran Yang, Tao Chen, Yuan Fu, Yeyi Li, Xianlong Fang, Kangjian Zhang, Jianju Zhang, Hui Li, Xueping Cao, Jinfa Gu, Jianwen Xiao, Qi Zhang, Xinyuan Liu, Qiujing Yu, Ting Wang.
      Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.
    DOI:  https://doi.org/10.1038/s41467-021-22173-5
  17. Science. 2021 Apr 02. 372(6537): 34-35
    Reversal of exhaustion in engineered T cells.
    Maksim Mamonkin, Malcolm K Brenner.
      
    DOI:  https://doi.org/10.1126/science.abh0583
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