bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒08‒23
thirty-four papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research


  1. JCI Insight. 2020 Aug 20. pii: 138729. [Epub ahead of print]5(16):
    Beckermann KE, Hongo R, Ye X, Young K, Carbonell K, Healey DCC, Siska PJ, Barone S, Roe CE, Smith CC, Vincent BG, Mason FM, Irish JM, Rathmell WK, Rathmell JC.
      Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells in tumor microenvironments. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reducing the effector function of renal cell carcinoma (RCC) CD8+ tumor-infiltrating lymphocytes (TILs). Here we define the role of these metabolic pathways in the activation and effector functions of CD8+ RCC TILs. CD28 costimulation plays a key role in augmenting T cell activation and metabolism, and is antagonized by the inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8+ TILs were activated at a low level when stimulated through the T cell receptor alone, addition of CD28 costimulation greatly enhanced activation, function, and proliferation. CD28 costimulation reprogrammed RCC CD8+ TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, possibly through upregulation of GLUT3. Mitochondria also fused to a greater degree, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8+ TIL activation and function. These data show that CD28 costimulation can restore RCC CD8+ TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.
    Keywords:  Glucose metabolism; Immunology; Immunotherapy; Oncology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.138729
  2. Trends Cell Biol. 2020 Aug 13. pii: S0962-8924(20)30143-4. [Epub ahead of print]
    Borghesan M, Hoogaars WMH, Varela-Eirin M, Talma N, Demaria M.
      Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. From their initial discovery in the 1960s, senescent cells have been hypothesized as potential contributors to the age-associated loss of regenerative potential. Here, we discuss recent evidence that implicates cellular senescence as a central regulatory mechanism of the aging process. We provide a comprehensive overview of age-associated pathologies in which cellular senescence has been implicated. We describe mechanisms by which senescent cells drive aging and diseases, and we discuss updates on exploiting these mechanisms as therapeutic targets. Finally, we critically analyze the use of senotherapeutics and their translation to the clinic, highlighting limitations and suggesting ideas for future applications and developments.
    Keywords:  SASP,; aging; cellular senescence; senescence hallmarks; senotherapeutics
    DOI:  https://doi.org/10.1016/j.tcb.2020.07.002
  3. Curr Opin Immunol. 2020 Aug 17. pii: S0952-7915(20)30075-3. [Epub ahead of print]67 27-35
    Piccirillo CA.
      Foxp3+ regulatory T (Treg) cells are the major gatekeepers of the immune system for the maintenance of self-tolerance and immune homeostasis. Treg cell development rests on the key activities of the master-switch transcription factor, Foxp3, which establishes the essential core program that defines Treg cell lineage identity in the thymus and peripheral tissues. Moreover, Foxp3+ Treg cells integrate a variety of inflammatory signals from the tissue microenvironment to engage specialized pathways in order to adapt their suppressive functions in situ. CD4 + Treg cell subsets possess mechanisms to control both gene transcription and mRNA translation. Ultimately, the resulting proteome orchestrates distinct cellular processes that poise Treg cell subsets to respond to inflammatory signals in a timely and context-dependent manner in lymphoid and non-lymphoid tissues for a coordinated modulation of immunity. Thus, understanding how Treg cells control their cellular adaptation in lymphoid and non-lymphoid tissues may reveal therapeutic targets for the treatment of autoimmunity and chronic inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.coi.2020.07.006
  4. Cell Rep. 2020 Aug 18. pii: S2211-1247(20)31033-0. [Epub ahead of print]32(7): 108048
    Maqbool MA, Pioger L, El Aabidine AZ, Karasu N, Molitor AM, Dao LTM, Charbonnier G, van Laethem F, Fenouil R, Koch F, Lacaud G, Gut I, Gut M, Amigorena S, Joffre O, Sexton T, Spicuglia S, Andrau JC.
      During thymic development and upon peripheral activation, T cells undergo extensive phenotypic and functional changes coordinated by lineage-specific developmental programs. To characterize the regulatory landscape controlling T cell identity, we perform a wide epigenomic and transcriptional analysis of mouse thymocytes and naive CD4 differentiated T helper cells. Our investigations reveal a dynamic putative enhancer landscape, and we could validate many of the enhancers using the high-throughput CapStarr sequencing (CapStarr-seq) approach. We find that genes using multiple promoters display increased enhancer usage, suggesting that apparent "enhancer redundancy" might relate to isoform selection. Furthermore, we can show that two Runx3 promoters display long-range interactions with specific enhancers. Finally, our analyses suggest a novel function for the PRC2 complex in the control of alternative promoter usage. Altogether, our study has allowed for the mapping of an exhaustive set of active enhancers and provides new insights into their function and that of PRC2 in controlling promoter choice during T cell differentiation.
    Keywords:  CapSTARR-seq; T cell enhancerome; enhancer and promoter usage; enhancer redundancy; long-distance enhancer-promoter interactions
    DOI:  https://doi.org/10.1016/j.celrep.2020.108048
  5. Gastroenterology. 2020 Aug 16. pii: S0016-5085(20)35056-3. [Epub ahead of print]
    Gasparetto M, Payne F, Nayak K, Kraiczy J, Glemas C, Philip-McKenzie Y, Ross A, Edgar RD, Zerbino DR, Salvestrini C, Torrente F, Ventham NT, Kalla R, Satsangi J, Sarkies P, Heuschkel R, Zilbauer M.
      BACKGROUND & AIMS: Gene expression patterns of CD8+ T cells have been reported to correlate with clinical outcomes of adults with inflammatory bowel diseases (IBD). We aimed at validating these findings in independent patient cohorts.METHODS: We obtained peripheral blood samples from 112 children with a new diagnosis of IBD (71 with Crohn's disease and 41 with ulcerative colitis) and 19 children without IBD (controls) and recorded medical information on disease activity and outcomes. CD8+ T cells were isolated from blood samples by magnetic bead sorting at the point of diagnosis and during the course of disease. Genome-wide transcription (n=192) and DNA methylation (n=66) profiles were generated using Affymetrix and Illumina arrays, respectively. Publicly available transcriptomes and DNA methylomes of CD8+ T cells from three adult patient cohorts with and without IBD were included in data analyses.
    RESULTS: Previously reported CD8+ T cell prognostic expression and exhaustion signatures were only found in the original adult IBD patient cohort. These signatures could not be detected either in a pediatric, or in a second adult IBD cohort. In contrast, an association between CD8+ T cell gene expression with age and sex was detected across all three cohorts. CD8+ gene transcription was clearly associated with IBD in the two cohorts that included non-IBD controls. Lastly, DNA methylation profiles of CD8+ T cells from children with Crohn's disease correlated with age but not with disease outcome.
    CONCLUSIONS: We were unable to validate previously reported findings of an association between CD8+ T cell gene transcription and disease outcome in IBD. Our findings reveal the challenges of developing prognostic biomarkers for patients with IBD and the importance of their validation in large, independent cohorts before clinical application.
    Keywords:  biomarker; epigenetic; prognosis; validation
    DOI:  https://doi.org/10.1053/j.gastro.2020.08.017
  6. J Lipid Atheroscler. 2020 Jan;9(1): 79-91
    Shimizu I, Minamino T.
      Cell-proliferation potency is limited, as cells cannot proceed through the cell cycle continually. Instead, they eventually show an irreversible arrest of proliferation, commonly referred to as cellular senescence. Following the initial discovery of this phenomenon by Hayflick et al., studies have indicated that cells are also destined to undergo aging. In addition to the irreversible termination of proliferation, senescent cells are characterized by a flattened and enlarged morphology. Senescent cells become pro-inflammatory and contribute to the initiation and maintenance of sustained chronic sterile inflammation. Aging is associated with the accumulation of senescent cells in the cardiovascular system, and in general these cells are considered to be pathogenic because they mediate vascular remodeling. Recently, genetic and pharmacological approaches have enabled researchers to eliminate senescent cells both in vitro and in vivo. The term "senolysis" is now used to refer to the depletion of senescent cells, and evidence indicates that senolysis contributes to the reversal of age-related pathogenic phenotypes without the risk of tumorigenesis. The concept of senolysis has opened new avenues in research on aging, and senolysis may be a promising therapeutic approach for combating age-related disorders, including arterial diseases.
    Keywords:  Arterial diseases; Cellular senescence; Senolysis
    DOI:  https://doi.org/10.12997/jla.2020.9.1.79
  7. Elife. 2020 Aug 19. pii: e59166. [Epub ahead of print]9
    Walls JF, Subleski JJ, Palmieri EM, Gonzalez Cotto M, Gardiner CM, McVicar DW, Finlay DK.
      Natural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating changes in signal transduction pathways and cellular metabolism is essential for effective NK cells responses. The glycolytic enzyme Pyruvate Kinase Muscle 2 (PKM2) has described roles in regulating glycolytic flux and signal transduction, particularly gene transcription. While PKM2 expression is robustly induced in activated NK cells, mice lacking PKM2 in NK cells showed no defect in NK cell metabolism, transcription or anti-viral responses to MCMV infection. NK cell metabolism was maintained due to compensatory PKM1 expression in PKM2-null NK cells. To further investigate the role of PKM2 we used TEPP-46, which increases PKM2 catalytic activity while inhibiting any PKM2 signalling functions. NK cells activated with TEPP-46 had reduced effector function due to TEPP-46-induced increases in oxidative stress. Overall, PKM2-regulated glycolytic metabolism and redox status, not transcriptional control, facilitate optimal NK cells responses.
    Keywords:  cell biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.59166
  8. Nat Cancer. 2020 May;1(5): 546-561
    Ghorani E, Reading JL, Henry JY, de Massy MR, Rosenthal R, Turati V, Joshi K, Furness AJS, Aissa AB, Saini SK, Ramskov S, Georgiou A, Sunderland MW, Wong YNS, De Mucha MV, Day W, Galvez-Cancino F, Becker PD, Uddin I, Ismail M, Ronel T, Woolston A, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Litchfield K, Conde L, Guerra-Assunção JA, Blighe K, Biswas D, Salgado R, Lund T, Al Bakir M, Moore DA, Hiley CT, Loi S, Sun Y, Yuan Y, AbdulJabbar K, Turajilic S, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Chain B, Swanton C, Quezada SA.
      Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
    DOI:  https://doi.org/10.1038/s43018-020-0066-y
  9. Mol Aspects Med. 2020 Aug 16. pii: S0098-2997(20)30057-1. [Epub ahead of print] 100888
    Vuononvirta J, Marelli-Berg FM, Poobalasingam T.
      In order to fulfill their effector and patrolling functions, lymphocytes traffic through the body and need to adapt to different tissue microenvironments. First, mature lymphocytes egress the bone marrow and the thymus into the vascular system. Circulating lymphocytes can exit the vasculature and penetrate into the tissues, either for patrolling in search for pathogens or to eliminate infection and activate the adaptive immune response. The cytoskeletal reorganization necessary to sustain migration require high levels of energy thus presenting a substantial bioenergetic challenge to migrating cells. The metabolic regulation of lymphocyte motility and trafficking has only recently begun to be investigated. In this review we will summarize current knowledge of the crosstalk between cell metabolism and the cytoskeleton in T lymphocytes, and discuss the concept that lymphocyte metabolism may reprogram in response to migratory stimuli and adapt to the different environmental cues received during recirculation in tissues.
    DOI:  https://doi.org/10.1016/j.mam.2020.100888
  10. Methods Mol Biol. 2020 ;2184 215-224
    Masson JJR, Ostrowski M, Duette G, Lee MKS, Murphy AJ, Crowe SM, Palmer CS.
      The analysis of mitochondrial dynamics within immune cells allows us to understand how fundamental metabolism influences immune cell functions, and how dysregulated immunometabolic processes impact biology and disease pathogenesis. For example, during infections, mitochondrial fission and fusion coincide with effector and memory T-cell differentiation, respectively, resulting in metabolic reprogramming. As frozen cells are generally not optimal for immunometabolic analyses, and given the logistic difficulties of analysis on cells within a few hours of blood collection, we have optimized and validated a simple cryopreservation protocol for peripheral blood mononuclear cells, yielding >95% cellular viability, as well as preserved metabolic and immunologic properties. Combining fluorescent dyes with cell surface antibodies, we demonstrate how to analyze mitochondrial density, membrane potential, and reactive oxygen species production in CD4 and CD8 T cells from cryopreserved clinical samples.
    Keywords:  CD4 and CD8 T cells; Immunometabolism; Mitochondrial density; Mitochondrial membrane potential; ROS
    DOI:  https://doi.org/10.1007/978-1-0716-0802-9_15
  11. Science. 2020 Aug 21. 369(6506): 942-949
    Payne KK, Mine JA, Biswas S, Chaurio RA, Perales-Puchalt A, Anadon CM, Costich TL, Harro CM, Walrath J, Ming Q, Tcyganov E, Buras AL, Rigolizzo KE, Mandal G, Lajoie J, Ophir M, Tchou J, Marchion D, Luca VC, Bobrowicz P, McLaughlin B, Eskiocak U, Schmidt M, Cubillos-Ruiz JR, Rodriguez PC, Gabrilovich DI, Conejo-Garcia JR.
      Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.
    DOI:  https://doi.org/10.1126/science.aay2767
  12. Int Immunopharmacol. 2020 Aug 14. pii: S1567-5769(20)31857-9. [Epub ahead of print]88 106877
    Wang B, Chen S, Qian H, Zheng Q, Chen R, Liu Y, Shi G.
      Though macrophages and neutrophils are considered to be the principal immune cells involved in gout inflammation, recent studies highlight an emerging role of T cell subsets in the pathogenesis of gout. Some studies found that abnormal functions of several T cell subsets and aberrant expressions of their signature cytokines existed in gouty arthritis. Additionally, recent studies also suggested that therapeutic strategies by targeting pro-inflammatory T cell subsets or their related cytokines could ameliorate monosodium urate (MSU) crystals-induced arthritis in mice. The important role of T cells in gouty arthritis may provide some explanation for the absence of acute gout attacks among individuals with severe hyperuricemia or clinical evidence of MSU crystals deposition. Nevertheless, the molecular mechanisms underlying the role of those T cell subsets in gouty arthritis and their role in the initiation, progression and resolution of gouty arthritis are largely elusive, which need to be elaborated in future research. Uncovering the role of those T cell subsets in gout may transform our understanding of gout and facilitate new promising preventive or therapeutic strategies for gouty arthritis.
    Keywords:  Gout; Pathogenesis; T cell subsets; Treatment targets
    DOI:  https://doi.org/10.1016/j.intimp.2020.106877
  13. J Immunol. 2020 Aug 17. pii: ji2000450. [Epub ahead of print]
    Villegas-Mendez A, Khandelwal G, McGowan LM, Dookie RS, Haley MJ, George C, Sims D, Lord GM, Sinclair LV, Jenner RG, Couper KN.
      CD4+ T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4+ T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4+ T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4+ T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4+ T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4+ T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4+ T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4+ T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4+ T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4+ T cells during malaria infection and other chronic conditions.
    DOI:  https://doi.org/10.4049/jimmunol.2000450
  14. Ageing Res Rev. 2020 Aug 15. pii: S1568-1637(20)30276-2. [Epub ahead of print] 101141
    Sharma R, Padwad Y.
      The role of increased tissue senescent cell (SC) burden in driving the process of ageing and associated disorders is rapidly gaining attention. Amongst various plausible factors, impairment in immune functions is emerging as a critical regulator of known age-associated accumulation of SC. Immune cells dysfunctions with age are multi-faceted and are uniquely attributed to the independent processes of immunosenescence and cellular senescence which may collectively impair immune system mediated clearance of SC. Moreover, being functionally and phenotypically heterogenic, immune cells are also liable to be affected by senescence microenvironment in other tissues. Therefore, strategies aimed at improving immunosenescence and cellular senescence in immune cells can have pleiotropic effects on ageing physiology including the accumulation of SC. In this regard, nutraceutical's immunomodulatory attributes are well documented which may have implications in developing nutrition-oriented immunotherapeutic approaches against SC. In particular, the three diverse sources of bioactive ingredients, viz., phytochemicals, probiotic bacteria and omega-3-fatty acids have shown promising anti-immunosenescence and anti-cellular senescence potential in immune cells influencing aging and immunity in ways beyond modest stimulation of immune responses. The present narrative review describes the preventive and therapeutic attributes of phytochemicals such as polyphenols, probiotic microbes and omega-3-fatty acids in influencing the emerging nexus of immunosenescence, cellular senescence and SC during aging. Outstanding questions and nutraceuticals-based pro-longevity and niche research areas have been deliberated. Further research using integrative approaches is recommended for developing nutrition-based holistic immunotherapeutic strategies for 'healthy ageing'.
    Keywords:  cellular senescence; immunosenescence; omega-3-fatty acids; phytochemicals; probiotics
    DOI:  https://doi.org/10.1016/j.arr.2020.101141
  15. Autophagy. 2020 Aug 20.
    Oh DS, Park JH, Jung HE, Kim HJ, Lee HK.
      Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections in infants. Macroautophagy/autophagy is a catalytic metabolic process required for cellular homeostasis. Although intracellular metabolism is important for immune responses in dendritic cells, the link between autophagy and immunometabolism remains unknown. Here, we show that the autophagy-related protein ATG5 regulates immunometabolism. Atg5-deficient mouse dendritic cells showed increased CD8A+ T-cell response and increased secretion of proinflammatory cytokines upon RSV infection. Transcriptome analysis showed that Atg5 deficiency alters the expression of metabolism-related genes. Atg5-deficient dendritic cells also showed increased activation of glycolysis and the AKT-MTOR-RPS6KB pathway and decreased mitochondrial activity, all of which are cellular signatures for metabolic activation. These cells also showed elevated CD8A+ T-cell priming and surface major histocompatibility complex (MHC) class I expression. Our results suggested that ATG5 regulated host immune responses by modulating dendritic cell metabolism. These findings may help develop potential antiviral therapies that alter host immunity by regulating autophagy and immunometabolism.
    Keywords:  ATG5; RSV; autophagy; dendritic cell metabolism; immunometabolism
    DOI:  https://doi.org/10.1080/15548627.2020.1812218
  16. Immunol Invest. 2020 Aug 20. 1-11
    Jin Z, Lan T, Zhao Y, Du J, Chen J, Lai J, Xu L, Chen S, Zhong X, Wu X, Li Y.
      The diverse structural and functional heterogeneity of γδ T cells is related to their distinct role in cancer immunity. The different phenotypes of γδ T cells in patients with acute myeloid leukemia (AML) is far from clear. In particular, the expression pattern of co-inhibitory and co-stimulatory receptors on γδ T cells remains unknown. In this study, we analyzed the distribution of γδ T cell subsets by expression of the immune checkpoint co-inhibitor TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) and its competing co-stimulatory receptor CD226 in AML patients of different clinical statuses (including de novo AML, AML in non-remission (NR), and AML in complete remission (CR)). Our data demonstrated an imbalanced distribution of TIGIT and CD226 on γδ T cells with a decrease in CD226+ γδ T cells and an increase in TIGIT+ γδ T cells in de novo AML patients, while TIGIT-CD226+ γδ T cells were restored in AML patients who achieved CR after chemotherapy. Moreover, the patients who had higher TIGIT+CD226- γδ T cells showed lower overall survival rate for non-M3 AML, which may be considered a novel prognostic immune biomarker. In conclusion, our study reveals for the first time that imbalance in the TIGIT/CD226 axis might be related to different clinical outcomes for AML patients.ABBREVIATIONS: AML: acute myeloid leukemia; CR: complete remission; ICs: immune checkpoints; PD-1: programmed death-1; γδ T cells: gamma delta T cells; TCR: T cell receptor; MHC: major histocompatibility complex; TIGIT: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; NK: natural killer; PB: Peripheral blood; NR: non-remission; FAB: French-American-British; WHO: World Health Organization; HIs: healthy individuals; OS: overall survival.
    Keywords:  Acute myeloid leukemia; CD226; TIGIT; γδ T cells
    DOI:  https://doi.org/10.1080/08820139.2020.1806868
  17. Mech Ageing Dev. 2020 Aug 17. pii: S0047-6374(20)30130-5. [Epub ahead of print] 111334
    Wan Y, Finkel T.
      Mitochondrial dysfunction and stem cell exhaustion are among the nine separate hallmarks of aging. Emerging evidence however suggests that mitochondrial activity can have a profound influence on the self-renewal and function of stem cells, thus mechanistically linking mitochondrial function and stem cell decline. In this review, we discuss how accumulation of mtDNA mutations or alterations in mitochondrial dynamics, turnover, and signaling can modulate age-dependent stem cell function. Finally, we also describe how mitochondrial substrate utilization influences stem and progenitor activity. Together, this growing body of evidence suggests that modulation of mitochondrial activity might provide a strategy to slow or reverse age-dependent stem cell decline, and potentially, slow or reverse human aging.
    DOI:  https://doi.org/10.1016/j.mad.2020.111334
  18. Curr Opin Immunol. 2020 Aug 15. pii: S0952-7915(20)30070-4. [Epub ahead of print]67 18-26
    Buszko M, Shevach EM.
      CD4+ Foxp3+ T Regulatory (Treg) cells play a critical role in the homeostasis and maintenance of the immune system. The understanding of different aspects of Treg cells biology remains an intensively investigated subject as altering their generation, stability, or function by drugs or biologics may have therapeutic value in the treatment of autoimmune and inflammatory diseases as well as cancers. This review will focus on recent studies on the role of cytokines, T Cell Receptor (TCR) and co-stimulatory/co-inhibitory molecules signaling, location and metabolism on the homeostasis and stability of Treg cells. The potential for therapeutic manipulation of each of these factors will be discussed.
    DOI:  https://doi.org/10.1016/j.coi.2020.07.001
  19. Int J Mol Sci. 2020 Aug 14. pii: E5845. [Epub ahead of print]21(16):
    Bleve A, Durante B, Sica A, Consonni FM.
      Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.
    Keywords:  cancer immunotherapy; cholesterol; fatty acids; lipid metabolism; myeloid-derived suppressor cells (MDSCs); obesity; tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/ijms21165845
  20. Methods Mol Biol. 2020 ;2184 233-263
    Sheppard AD, Lysaght J.
      The last century of research in tumor immunology has culminated in the advent of immunotherapy, most notably immune checkpoint inhibitors. These drugs have shown encouraging results across a multitude of malignancies and have shifted the paradigm of cancer treatment. However, no more than 40% of patients treated with these immune checkpoint blockade inhibitors respond. Thus, resistance is a barrier to therapy that remains poorly understood. All cells require energy and biosynthetic precursors for survival, growth, and functioning, where multiple metabolic pathways allow for flexibility in how nutrients are utilized. A defining hallmark of many cancers is altered cellular metabolism, creating an imbalanced demand for nutrients within the tumor microenvironment. Immunometabolism is increasingly understood to be vital to the functions and phenotypes of a myriad of immune cell subsets. In tumors, the high demand for nutrients by the tumor drives competition between tumor cells and infiltrating immune cells, culminating in dysfunctional immune responses. This chapter discusses the recent successes in cancer immunotherapy and highlights challenges to therapy. We also outline the major metabolic processes involved in the generation of an immune response, how this can become dysregulated in the context of the tumor microenvironment, and how this contributes to resistance to immunotherapy. Finally, we explore the potential for targeting immunometabolic pathways to improve immunotherapy, and examine current trials targeting various aspects of metabolism in an attempt to improve the outcomes from immunotherapy.
    Keywords:  Immunometabolism; Immunotherapy; Metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-0802-9_17
  21. Dev Cell. 2020 Aug 10. pii: S1534-5807(20)30589-X. [Epub ahead of print]
    Frame JM, Kubaczka C, Long TL, Esain V, Soto RA, Hachimi M, Jing R, Shwartz A, Goessling W, Daley GQ, North TE.
      Embryonic hematopoietic stem and progenitor cells (HSPCs) robustly proliferate while maintaining multilineage potential in vivo; however, an incomplete understanding of spatiotemporal cues governing their generation has impeded robust production from human induced pluripotent stem cells (iPSCs) in vitro. Using the zebrafish model, we demonstrate that NLRP3 inflammasome-mediated interleukin-1-beta (IL1β) signaling drives HSPC production in response to metabolic activity. Genetic induction of active IL1β or pharmacologic inflammasome stimulation increased HSPC number as assessed by in situ hybridization for runx1/cmyb and flow cytometry. Loss of inflammasome components, including il1b, reduced CD41+ HSPCs and prevented their expansion in response to metabolic cues. Cell ablation studies indicated that macrophages were essential for initial inflammasome stimulation of Il1rl1+ HSPCs. Significantly, in human iPSC-derived hemogenic precursors, transient inflammasome stimulation increased multilineage hematopoietic colony-forming units and T cell progenitors. This work establishes the inflammasome as a conserved metabolic sensor that expands HSPC production in vivo and in vitro.
    Keywords:  IL1β; Nlrp3; endothelial-to-hematopoietic transition (EHT); hematopoietic stem cell (HSC); iPSC; inflammasome; inflammation; zebrafish
    DOI:  https://doi.org/10.1016/j.devcel.2020.07.015
  22. Curr Opin Rheumatol. 2020 Aug 19.
    Romo-Tena J, Kaplan MJ.
      PURPOSE OF REVIEW: To provide an update on state-of-the-art evidence on the role of immunometabolism reprogramming in the pathogenesis of systemic lupus erythematosus (SLE).RECENT FINDINGS: Mitochondrial dysfunction and enhanced oxidative stress, along with specific defects in other metabolic pathways, can promote dysregulation of innate and adaptive immune responses in SLE. These abnormalities appear to be driven by genetic and epigenetic factors, modulated by stochastic events. In addition to extensive descriptions of abnormalities in immunometabolism of lupus lymphocytes, recent studies support the critical role of dysregulation of metabolic pathways in innate immune cells including neutrophils, macrophages and dendritic cells, in SLE pathogenesis. Recent abnormalities described in lipid metabolism have been associated with SLE disease activity and related damage. Promising therapeutic strategies that target these metabolic abnormalities have recently been described in SLE.
    SUMMARY: Fundamental new insights regarding the role of mitochondrial dysfunction in innate immune dysregulation in SLE pathogenesis have recently emerged. Defects in specific molecular pathways pertinent to immunometabolism in SLE have been described. New insights in translational medicine and promising therapeutic targets have been proposed based on these recent findings.
    DOI:  https://doi.org/10.1097/BOR.0000000000000738
  23. Cancers (Basel). 2020 Aug 14. pii: E2274. [Epub ahead of print]12(8):
    Saka D, Gökalp M, Piyade B, Cevik NC, Arik Sever E, Unutmaz D, Ceyhan GO, Demir IE, Asimgil H.
      T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.
    Keywords:  PDAC; T-cell exhaustion; TME; TOXs; Thymocyte selection-associated high mobility group box protein; epigenetics; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers12082274
  24. Nat Commun. 2020 Aug 17. 11(1): 4113
    Wu H, Estrella V, Beatty M, Abrahams D, El-Kenawi A, Russell S, Ibrahim-Hashim A, Longo DL, Reshetnyak YK, Moshnikova A, Andreev OA, Luddy K, Damaghi M, Kodumudi K, Pillai SR, Enriquez-Navas P, Pilon-Thomas S, Swietach P, Gillies RJ.
      The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.
    DOI:  https://doi.org/10.1038/s41467-020-17756-7
  25. Eur J Cell Biol. 2020 Aug;pii: S0171-9335(20)30047-9. [Epub ahead of print]99(6): 151108
    Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P.
      Cellular theory of aging states that human aging is the result of cellular aging, in which an increasing proportion of cells reach senescence. Senescence, from the Latin word senex, means "growing old," is an irreversible growth arrest which occurs in response to damaging stimuli, such as DNA damage, telomere shortening, telomere dysfunction and oncogenic stress leading to suppression of potentially dysfunctional, transformed, or aged cells. Cellular senescence is characterized by irreversible cell cycle arrest, flattened and enlarged morphology, resistance to apoptosis, alteration in gene expression and chromatin structure, expression of senescence associated- β-galactosidase (SA-β-gal) and acquisition of senescence associated secretory phenotype (SASP). In this review paper, different types of cellular senescence including replicative senescence (RS) which occurs due to telomere shortening and stress induced premature senescence (SIPS) which occurs in response to different types of stress in cells, are discussed. Biomarkers of cellular senescence and senescent assays including BrdU incorporation assay, senescence associated- β-galactosidase (SA-β-gal) and senescence-associated heterochromatin foci assays to detect senescent cells are also addressed.
    Keywords:  Aging; Cellular senescence; Replicative senescence; Senescence associated secretory phenotype (SASP); Senescence associated- β-galactosidase (SA-β-gal); Stress induced premature senescence
    DOI:  https://doi.org/10.1016/j.ejcb.2020.151108
  26. Nature. 2020 Aug 19.
    Gomes AP, Ilter D, Low V, Endress JE, Fernández-García J, Rosenzweig A, Schild T, Broekaert D, Ahmed A, Planque M, Elia I, Han J, Kinzig C, Mullarky E, Mutvei AP, Asara J, de Cabo R, Cantley LC, Dephoure N, Fendt SM, Blenis J.
      The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.
    DOI:  https://doi.org/10.1038/s41586-020-2630-0
  27. EBioMedicine. 2020 Aug 17. pii: S2352-3964(20)30319-4. [Epub ahead of print]59 102943
    Missiroli S, Perrone M, Genovese I, Pinton P, Giorgi C.
      Mitochondria are dynamic organelles that have essential metabolic activity and are regarded as signalling hubs with biosynthetic, bioenergetics and signalling functions that orchestrate key biological pathways. However, mitochondria can influence all processes linked to oncogenesis, starting from malignant transformation to metastatic dissemination. In this review, we describe how alterations in the mitochondrial metabolic status contribute to the acquisition of typical malignant traits, discussing the most recent discoveries and the many unanswered questions. We also highlight that expanding our understanding of mitochondrial regulation and function mechanisms in the context of cancer cell metabolism could be an important task in biomedical research, thus offering the possibility of targeting mitochondria for the treatment of cancer.
    Keywords:  Calcium; Cancer; Metabolism; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.ebiom.2020.102943
  28. Blood Adv. 2020 Aug 25. 4(16): 3927-3942
    Latis E, Michonneau D, Leloup C, Varet H, Peffault de Latour R, , Bianchi E, Socié G, Rogge L.
      The cellular and molecular processes involved in acute graft-versus-host disease (aGVHD) development early after allogeneic hematopoietic cell transplantation (HCT) in humans remain largely unknown. We have performed multiparameter immunophenotyping and molecular profiling of CD4+ and CD8+ T cells in 2 independent cohorts of patients undergoing HCT, as well as in their HLA-identical sibling donors. Cellular profiling using spectral flow cytometry showed an incomplete reconstitution of the T-cell compartment in recipients without aGVHD early after transplantation, as well as a shift toward an effector memory phenotype, paralleled by depletion of the naive T-cell pool. Molecular profiling of T-cell populations in donors vs recipients without aGVHD revealed increased pathway activity of >40 gene modules in recipients. These pathways were associated in particular with T-cell activation, adhesion, migration, and effector functions. Cellular profiles from recipients developing aGVHD displayed an enrichment of cells with a T memory stem cell-like phenotype compared with recipients without aGVHD. Comparison of gene profiles from these recipients revealed that transforming growth factor-β (TGF-β) signaling was most significantly downregulated, whereas the pathway activity of NF-κB-associated transcription factors and signaling pathways were increased, at aGVHD onset. This study suggests that the integration of cellular and molecular profiles provides new insights into the development of aGVHD in humans.
    DOI:  https://doi.org/10.1182/bloodadvances.2019001032
  29. Cold Spring Harb Perspect Biol. 2020 Aug 18. pii: a037762. [Epub ahead of print]
    Takamura S.
      Tissue-resident memory T cells (Trm) comprise the majority of memory cells in nonlymphoid tissues and play a predominant role in immunity at barrier surfaces. A better understanding of Trm cell maintenance and function is essential for the development of vaccines that confer frontline protection. However, it is currently challenging to precisely distinguish Trm cells from other T cells, and this has led to confusion in the literature. Here we highlight gaps in our understanding of tissue memory and discuss recent advances in the classification of Trm cell subsets based on their distribution and functional characteristics.
    DOI:  https://doi.org/10.1101/cshperspect.a037762
  30. BMC Immunol. 2020 Aug 20. 21(1): 48
    Lee MJ, Yun SJ, Lee B, Jeong E, Yoon G, Kim K, Park S.
      BACKGROUND: T cell activation is associated with increase in glycolysis and glutaminolysis. T cell immunoglobulin and mucin domain containing protein-3 (TIM-3), a T cell surface molecule, downregulates T cell activation and leads to insufficient immunity in cancer and chronic infection. TIM-3 regulates T cell activation possibly through alterations in metabolism; however, the relationship between TIM-3 expression and T cell metabolic changes has not been well studied.RESULTS: We investigated the association between TIM-3 expression and metabolic changes by analyzing glucose metabolism, glutamine metabolism, and mitochondrial function in TIM-3 overexpressing or knockout Jurkat T cell lines relative to their control cell lines. Glucose uptake and consumption, and lactate release were downregulated by TIM-3 expression but upregulated by TIM-3 knockout. Concomitantly, the expression of the glucose transporter, Glut1, but not Glut2, 3, or 4 was altered by TIM-3 expression. However, TIM-3 expression alone could not account for the change in glutamine consumption, glutamate release, and mitochondrial mass, ROS production or membrane potential in these cell lines.
    CONCLUSION: Our results show the association of TIM-3 expression with T cell glucose metabolism. These results are significant in chronic infections and cancers where it is necessary to control TIM-3 expressing T cells.
    Keywords:  CD4+ T cell; Glucose transporter; Glutaminolysis; Glycolysis; HAVCR2
    DOI:  https://doi.org/10.1186/s12865-020-00377-6
  31. FASEB J. 2020 Aug 17.
    Marchetti P, Fovez Q, Germain N, Khamari R, Kluza J.
      Mitochondrial metabolism must constantly adapt to stress conditions in order to maintain bioenergetic levels related to cellular functions. This absence of proper adaptation can be seen in a wide array of conditions, including cancer. Metabolic adaptation calls on mitochondrial function and draws on the mitochondrial reserve to meet increasing needs. Among mitochondrial respiratory parameters, the spare respiratory capacity (SRC) represents a particularly robust functional parameter to evaluate mitochondrial reserve. We provide an overview of potential SRC mechanisms and regulation with a focus on its particular significance in cancer cells.
    Keywords:  mitochondrial adaptation; mitochondrial dysfunction; mitochondrial flexibility; mitochondrial metabolism; mitochondrial stress; oxygen consumption; respiratory reserve capacity; spare reserve capacity; uncoupling ratio
    DOI:  https://doi.org/10.1096/fj.202000767R
  32. Hum Mol Genet. 2020 Aug 21. pii: ddaa189. [Epub ahead of print]
    Mejia-Ramirez E, Geiger H, Florian MC.
      Changes of polarity in somatic stem cells upon aging or disease lead to a functional deterioration of stem cells and consequently loss of tissue homeostasis, likely due to changes in the mode (symmetry vs. asymmetry) of stem cell divisions. Changes in polarity of epigenetic markers (or 'epi-polarity') in stem cells, which are linked to alterations in chromatin architecture, might explain how a decline in the frequency of epi-polar stem cells can have a long-lasting impact on the function of especially aging stem cells. The drift in epi-polarity might represent a novel therapeutic target to improve stem cell function upon aging or disease. Here we review basic biological principles of epigenetic polarity, with a special focus on epi-polarity and aging of hematopoietic stem cells.
    DOI:  https://doi.org/10.1093/hmg/ddaa189
  33. Biomolecules. 2020 Aug 18. pii: E1200. [Epub ahead of print]10(8):
    Wrzosek A, Augustynek B, Żochowska M, Szewczyk A.
      Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.
    Keywords:  ATP; ROS; calcium; mitochondria; potassium channel openers; potassium channels
    DOI:  https://doi.org/10.3390/biom10081200