bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒11‒01
nineteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research


  1. Curr Opin Physiol. 2020 Oct;17 207-223
    Wang Y, Tao A, Vaeth M, Feske S.
      T cells are an essential component of the immune system that provide antigen-specific acute and long lasting immune responses to infections and tumors, ascertain the maintenance of immunological tolerance and, on the flipside, mediate autoimmunity in a variety of diseases. The activation of T cells through antigen recognition by the T cell receptor (TCR) results in transient and sustained Ca2+ signals that are shaped by the opening of Ca2+ channels in the plasma membrane and cellular organelles. The dynamic regulation of intracellular Ca2+ concentrations controls a variety of T cell functions on the timescale of seconds to days after signal initiation. Among the more recently identified roles of Ca2+ signaling in T cells is the regulation of metabolic pathways that control the function of many T cell subsets. In this review, we discuss how Ca2+ regulates several metabolic programs in T cells such as the activation of AMPK and the PI3K-AKT-mTORC1 pathway, aerobic glycolysis, mitochondrial metabolism including tricarboxylic acid (TCA) cycle function and oxidative phosphorylation (OXPHOS), as well as lipid metabolism.
    DOI:  https://doi.org/10.1016/j.cophys.2020.07.016
  2. Front Immunol. 2020 ;11 593203
    Stairiker CJ, Thomas GD, Salek-Ardakani S.
      Enhancer of zeste 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that mediates di- and trimethylation of histone 3 lysine 27 effectively precluding successful gene transcription at these loci. This class of epigenetic modifications facilitates the maintenance of tissue-specific cellular transcriptional programs as cells undergoing successive rounds of proliferation. CD8+ T cells are effective mediators of adaptive immunity and function to eliminate virus- and bacteria-infected cells as well as tumor cells. Upon recognition of cognate antigen, T cells undergo activation/proliferation to clear the target cells. The heterogeneous population of responding T cells formed during these proliferative events thus rely on epigenetic modifications to ensure identity and confer functional capabilities. In this review, we will focus on the role of the dynamic expression EZH2 in shaping the epigenetic landscape of CD8+ T cell fate and function, with a particular emphasis on infection and cancer. We also explore competing hypotheses pertaining to EZH2 function and the prospects of clinical EZH2 inhibitors in fine-tuning T cell responses.
    Keywords:  CD8 lymphocytes +; EZH2; cancer; cell fate and differentiation; effector; enhancer of zeste homolog 2; memory; virus
    DOI:  https://doi.org/10.3389/fimmu.2020.593203
  3. Int J Mol Sci. 2020 Oct 27. pii: E7972. [Epub ahead of print]21(21):
    Balyan R, Gautam N, Gascoigne NRJ.
      Understanding the various mechanisms that govern the development, activation, differentiation, and functions of T cells is crucial as it could provide opportunities for therapeutic interventions to disrupt immune pathogenesis. Immunometabolism is one such area that has garnered significant interest in the recent past as it has become apparent that cellular metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate, and differentiate. In each phase of the lifespan of a T-cell, cellular metabolism has to be tailored to match the specific functional requirements of that phase. Resting T cells rely on energy-efficient oxidative metabolism but rapidly shift to a highly glycolytic metabolism upon activation in order to meet the bioenergetically demanding process of growth and proliferation. However, upon antigen clearance, T cells return to a more quiescent oxidative metabolism to support T cell memory generation. In addition, each helper T cell subset engages distinct metabolic pathways to support their functional needs. In this review, we provide an overview of the metabolic changes that occur during the lifespan of a T cell and discuss several important studies that provide insights into the regulation of the metabolic landscape of T cells and how they impact T cell development and function.
    Keywords:  CD4 T cell differentiation; T cell; T cell activation; aerobic glycolysis; fatty acid oxidation; immunometabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms21217972
  4. Immunometabolism. 2020 Oct 16. 2(4): e200035
    Schroth J, Henson SM.
      We review here the seminal findings of Desdin-Mico et al. showing that T cells with dysfunctional mitochondria induce multimorbity and premature senescence, due to mitochondrial transcription factor A (TFAM). They add further weight to the idea that targeting immunometabolism could be beneficial in combating the detrimental effects of age-related disease.
    Keywords:  T cell; ageing; metabolism; mitochondria; senescence
    DOI:  https://doi.org/10.20900/immunometab20200035
  5. Sci Transl Med. 2020 Oct 28. pii: eabb8969. [Epub ahead of print]12(567):
    Uhl FM, Chen S, O'Sullivan D, Edwards-Hicks J, Richter G, Haring E, Andrieux G, Halbach S, Apostolova P, Büscher J, Duquesne S, Melchinger W, Sauer B, Shoumariyeh K, Schmitt-Graeff A, Kreutz M, Lübbert M, Duyster J, Brummer T, Boerries M, Madl T, Blazar BR, Groß O, Pearce EL, Zeiser R.
      Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post-allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.
    DOI:  https://doi.org/10.1126/scitranslmed.abb8969
  6. Cancers (Basel). 2020 Oct 28. pii: E3164. [Epub ahead of print]12(11):
    Slaney CY, Kershaw MH.
      Using immunotherapy to treat cancers can be traced back to the 1890s, where a New York physician William Coley used heat-killed bacteria to treat cancer patients, which became known as "Coley's toxin" [...].
    Keywords:  CAR T cells; PD-1; immune checkpoint inhibitors; immunotherapy; microenvironment
    DOI:  https://doi.org/10.3390/cancers12113164
  7. Int J Mol Sci. 2020 Oct 26. pii: E7941. [Epub ahead of print]21(21):
    Dong L, Gopalan V, Holland O, Neuzil J.
      Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.
    Keywords:  anti-cancer strategy; drug delivery; mitocans; mitochondrial targeting
    DOI:  https://doi.org/10.3390/ijms21217941
  8. Int J Mol Sci. 2020 Oct 27. pii: E7969. [Epub ahead of print]21(21):
    Kolawole EM, Lamb TJ, Evavold BD.
      T cells are critical for a functioning adaptive immune response and a strong correlation exists between T cell responses and T cell receptor (TCR): peptide-loaded MHC (pMHC) binding. Studies that utilize pMHC tetramer, multimers, and assays of three-dimensional (3D) affinity have provided advancements in our understanding of T cell responses across different diseases. However, these technologies focus on higher affinity and avidity T cells while missing the lower affinity responders. Lower affinity TCRs in expanded polyclonal populations almost always constitute a significant proportion of the response with cells mediating different effector functions associated with variation in the proportion of high and low affinity T cells. Since lower affinity T cells expand and are functional, a fully inclusive view of T cell responses is required to accurately interpret the role of affinity for adaptive T cell immunity. For example, low affinity T cells are capable of inducing autoimmune disease and T cells with an intermediate affinity have been shown to exhibit an optimal anti-tumor response. Here, we focus on how affinity of the TCR may relate to T cell phenotype and provide examples where 2D affinity influences functional outcomes.
    Keywords:  2D kinetics; T cells; TCR; affinity; bond lifetime; pMHC
    DOI:  https://doi.org/10.3390/ijms21217969
  9. Cancer Cell. 2020 Sep 23. pii: S1535-6108(20)30478-5. [Epub ahead of print]
    Kaymak I, Williams KS, Cantor JR, Jones RG.
      Immune cells' metabolism influences their differentiation and function. Given that a complex interplay of environmental factors within the tumor microenvironment (TME) can have a profound impact on the metabolic activities of immune, stromal, and tumor cell types, there is emerging interest to advance understanding of these diverse metabolic phenotypes in the TME. Here, we discuss cell-extrinsic contributions to the metabolic activities of immune cells. Then, considering recent technical advances in experimental systems and metabolic profiling technologies, we propose future directions to better understand how immune cells meet their metabolic demands in the TME, which can be leveraged for therapeutic benefit.
    Keywords:  immunology; immunometabolism; in vitro modeling; metabolism; metabolomics; physiologic media; stable isotope tracing; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2020.09.004
  10. Adv Exp Med Biol. 2020 ;1273 39-68
    Williams JB, Kupper TS.
      Tissue-resident memory T (TRM) cells are strategically positioned within the epithelial layers of many tissues to provide enduring site-specific immunological memory. This unique T-cell lineage is endowed with the capacity to rapidly respond to tissue perturbations and has a well-documented role in eradicating pathogens upon reexposure. Emerging evidence has highlighted a key role for TRM cells in cancer immunity. Single-cell approaches have identified TRM cells among other CD8+ tumor-infiltrating lymphocyte (TIL) subsets, and their presence is a positive indicator of clinical outcome in cancer patients. Furthermore, recent preclinical studies have elegantly demonstrated that TRM cells are a critical component of the antitumor immune response. Given their unique functional abilities, TRM cells have emerged as a potential immunotherapeutic target. Here, we discuss TRM cells in the framework of the cancer-immunity cycle and in the context of the T cell- and non-T cell-inflamed tumor microenvironments (TME). We highlight how their core features make TRM cells uniquely suited to function within the metabolically demanding TME. Finally, we consider potential therapeutic avenues that target TRM cells to augment the antitumor immune response.
    Keywords:  Antigen-presenting cells; Cancer; Immune exclusion; Immunity; Immunotherapy; Microenvironment; T cell dysfunction; Tissue-resident memory T cells
    DOI:  https://doi.org/10.1007/978-3-030-49270-0_3
  11. Nature. 2020 Oct 28.
    Shang M, Cappellesso F, Amorim R, Serneels J, Virga F, Eelen G, Carobbio S, Rincon MY, Maechler P, De Bock K, Ho PC, Sandri M, Ghesquière B, Carmeliet P, Di Matteo M, Berardi E, Mazzone M.
      Muscle regeneration is sustained by infiltrating macrophages and the consequent activation of satellite cells1-4. Macrophages and satellite cells communicate in different ways1-5, but their metabolic interplay has not been investigated. Here we show, in a mouse model, that muscle injuries and ageing are characterized by intra-tissue restrictions of glutamine. Low levels of glutamine endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity, at the expense of glutamine oxidation mediated by glutamate dehydrogenase 1 (GLUD1). Glud1-knockout macrophages display constitutively high GS activity, which prevents glutamine shortages. The uptake of macrophage-derived glutamine by satellite cells through the glutamine transporter SLC1A5 activates mTOR and promotes the proliferation and differentiation of satellite cells. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing. Conversely, SLC1A5 blockade in satellite cells or GS inactivation in macrophages negatively affects satellite cell functions and muscle regeneration. These results highlight the metabolic crosstalk between satellite cells and macrophages, in which macrophage-derived glutamine sustains the functions of satellite cells. Thus, the targeting of GLUD1 may offer therapeutic opportunities for the regeneration of injured or aged muscles.
    DOI:  https://doi.org/10.1038/s41586-020-2857-9
  12. Int J Mol Sci. 2020 Oct 27. pii: E7984. [Epub ahead of print]21(21):
    Mongelli A, Atlante S, Barbi V, Bachetti T, Martelli F, Farsetti A, Gaetano C.
      The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non-senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases.
    Keywords:  aging; apoptosis; chronic diseases; clinical trials; senescence; senolytics; senomorphics; senotherapeutics
    DOI:  https://doi.org/10.3390/ijms21217984
  13. Front Immunol. 2020 ;11 570041
    Steingold JM, Hatfield SM.
      The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling. Indeed, both inflamed and cancerous tissues are hypoxic and rich in extracellular adenosine, in part due to stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Adenosine signals through adenosine A2A receptors (A2AR) to suppress anti-tumor and anti-pathogen immune responses. Several classes of anti-hypoxia-A2AR therapeutics have been offered to refractory cancer patients, with A2AR blockers, inhibitors of adenosine-generating enzymes such as CD39 and CD73, and hypoxia-targeting drugs now reaching the clinical stage. Clinical results have confirmed preclinical observations that blockade of the hypoxia-adenosine-A2AR axis synergizes with inhibitors of immune checkpoints to induce tumor rejection. Thus, A2AR blockers provide a new hope for the majority of patients who are nonresponsive to current immunotherapeutic approaches including checkpoint blockade. Here, we discuss the discoveries that firmly implicate the A2AR as a critical and non-redundant biochemical negative regulator of the immune response and highlight the importance of targeting the hypoxia-adenosine-A2AR axis to manipulate anti-pathogen and anti-tumor immune responses.
    Keywords:  HIF−1α; T cell; adenosine; cancer immunotherapies; hypoxia; immune checkpoint; immunology
    DOI:  https://doi.org/10.3389/fimmu.2020.570041
  14. Front Immunol. 2020 ;11 565631
    Ponterio E, De Maria R, Haas TL.
      The chimeric antigen receptor (CAR) is an artificial molecule engineered to induce cytolytic T cell reactions in tumors. Generally, this molecule combines an extracellular single-chain variable fragment (scFv) able to recognize tumor-associated epitopes together with the intracellular signaling domains that are required for T cell activation. When expressed by T cells, the CAR enables the recognition and subsequent destruction of cancer cells expressing the complementary antigen on their surface. Although the clinical application for CAR T cells is currently limited to some hematological malignancies, researchers are trying to develop CAR T cell-based therapies for the treatment of solid tumors. However, while in the case of CD19, or other targets restricted to the hematopoietic compartment, the toxicity is limited and manageable, the scarcity of specific antigens expressed by solid tumors and not by healthy cells from vital organs makes the clinical development of CAR T cells in this context particularly challenging. Here we summarize relevant research and clinical trials conducted to redirect CAR T cells to surface antigens in solid tumors and cancer stem cells with a focus on colorectal cancer and glioblastoma. Finally, we will discuss current knowledge of altered glycosylation of CSCs and cancer cells and how these novel epitopes may help to target CAR T cell-based immunotherapy in the future.
    Keywords:  CAR T cells therapy; CRC (colorectal cancer); CSCs; GBM; MAbs; solid tumor
    DOI:  https://doi.org/10.3389/fimmu.2020.565631
  15. Front Immunol. 2020 ;11 592569
    Busselaar J, Tian S, van Eenennaam H, Borst J.
      Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) "exhaustion", i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These "predysfunctional" CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide "help" signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.
    Keywords:  CD4+ T cell; CD8+ T cell; cancer; dysfunction; exhaustion; infection
    DOI:  https://doi.org/10.3389/fimmu.2020.592569
  16. Cell Rep. 2020 Oct 27. pii: S2211-1247(20)31316-4. [Epub ahead of print]33(4): 108327
    Wu L, Lin W, Liao Q, Wang H, Lin C, Tang L, Lian W, Chen Z, Li K, Xu L, Zhou R, Ding Y, Zhao L.
      Abnormal activation of calcium channels has been shown to play crucial roles in tumor occurrence and development. However, the role of inhibitors targeting calcium channels in tumor progression and immune regulation remains unclear, and their clinical applications are still limited. We show that nifedipine (NIFE), a calcium channel blocker, inhibits calcium influx to impair nuclear factor of activated T cell 2 (NFAT2) dephosphorylation, activation, and nuclear translocation, thus preventing transcriptional activation of downstream signaling molecules to suppress colorectal cancer (CRC) proliferation and metastasis. In addition, NIFE decreases expression of programmed death-ligand 1 (PD-L1) on CRC cells and programmed death-1 (PD-1) on CD8+ T cells and reactivates tumor immune monitoring, which may stimulate or enhance PD-1-based antitumor immunotherapy. Our findings provide direct evidence that NIFE is a promising clinical therapy to treat patients with advanced CRC by affecting the tumor itself and tumor immunity. NIFE may be a promising therapeutic option to enhance effectiveness of immune checkpoint blockade therapy in CRC.
    Keywords:  colorectal cancer; nifedipine; nuclear factors of activated T cells 2; tumor immune; tumor metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2020.108327
  17. Proc Natl Acad Sci U S A. 2020 Oct 27. pii: 202004570. [Epub ahead of print]
    Zhou XA, Zhou J, Zhao L, Yu G, Zhan J, Shi C, Yuan R, Wang Y, Chen C, Zhang W, Xu D, Ye Y, Wang W, Shen Z, Wang W, Wang J.
      Aberrant programmed cell death protein 1 (PD-1) expression on the surface of T cells is known to inhibit T cell effector activity and to play a pivotal role in tumor immune escape; thus, maintaining an appropriate level of PD-1 expression is of great significance. We identified KLHL22, an adaptor of the Cul3-based E3 ligase, as a major PD-1-associated protein that mediates the degradation of PD-1 before its transport to the cell surface. KLHL22 deficiency leads to overaccumulation of PD-1, which represses the antitumor response of T cells and promotes tumor progression. Importantly, KLHL22 was markedly decreased in tumor-infiltrating T cells from colorectal cancer patients. Meanwhile, treatment with 5-fluorouracil (5-FU) could increase PD-1 expression by inhibiting the transcription of KLHL22. These findings reveal that KLHL22 plays a crucial role in preventing excessive T cell suppression by maintaining PD-1 expression homeostasis and suggest the therapeutic potential of 5-FU in combination with anti-PD-1 in colorectal cancer patients.
    Keywords:  5-FU; PD-1; immune checkpoint block therapy; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2004570117
  18. J Mol Endocrinol. 2020 Oct 01. pii: JME-20-0196.R1. [Epub ahead of print]
    Giguere V, Vernier M.
      Aging is a degenerative process that results from the accumulation of cellular and tissue lesions, leading progressively to organ dysfunction and death. Although the biological basis of human aging remains unclear, a large amount of data points to deregulated mitochondrial function as a central regulator of this process. Mounting years of research on aging support the notion that the engendered age-related decline of mitochondria is associated with alterations in key pathways that regulate mitochondrial biology. Particularly, several studies in the last decade have emphasized the importance of the estrogen-related receptor (ERR) family of nuclear receptors, master regulators of mitochondrial function, and their transcriptional coactivators PGC-1s in this context. In this review, we summarize key discoveries implicating the PGC-1/ERR axis in age-associated mitochondrial deregulation and tissue dysfunction. Also, we highlight the pharmacological potential of targeting the PGC-1/ERR axis to alleviate the onset of aging and its adverse effects.
    DOI:  https://doi.org/10.1530/JME-20-0196