bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020–10–18
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Regulatory t cell metabolism at the intersection between autoimmune diseases and cancer.
  2. Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity.
  3. Manipulation of Glucose Availability to Boost Cancer Immunotherapies.
  4. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance.
  5. Autophagy and Heat-Shock Response Impair Stress Granule Assembly during Cellular Senescence.
  6. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.
  7. Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche.
  8. Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans.
  9. Naive CD8+ T Cells Expressing CD95 Increase Human Cardiovascular Disease Severity.
  10. Signaling pathways and effectors of aging.
  11. Differences in Mitochondrial Membrane Potential Identify Distinct Populations of Human Cardiac Mesenchymal Progenitor Cells.
  12. Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.
  13. CAR-T cells as senolytic and antifibrotic therapy.
  14. Naive T-cell depletion in stem cell transplantation.
  15. 'Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity.
  16. Immunotherapy in older patients with cancer.
  17. Therapeutic potential of targeting mitochondrial dynamics in cancer.
  18. Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling.
  19. Non-canonical roles of NAMPT and PARP in inflammation.
  1. Eur J Immunol. 2020 Oct 16.
    Regulatory t cell metabolism at the intersection between autoimmune diseases and cancer.
    Henry Kurniawan, Leticia Soriano-Baguet, Dirk Brenner.
      Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg-intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies. This article is protected by copyright. All rights reserved.
    Keywords:  Regulatory T cells; autoimmunity; cancer; metabolism
    DOI:  https://doi.org/10.1002/eji.201948470
  2. Curr Opin Immunol. 2020 Oct 08. pii: S0952-7915(20)30086-8. [Epub ahead of print]67 57-67
    Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity.
    Mathias Pawlak, Allen W Ho, Vijay K Kuchroo.
      CD4+T helper (Th) cells are critical in homeostasis and host defense but are also central to the development of various autoimmune diseases if they become dysregulated. Specifically, pathogenic Th1 and Th17 cells contribute to autoimmune inflammation whereas Treg and Tr1 cells are important for maintaining immune tolerance and resolution of inflammation, respectively. Cytokines trigger signaling pathways in naive T cells that induce lineage-defining transcription factors that direct their differentiation into the distinct T helper cell subsets. It has become clear that the differentiation of T helper cells is not only influenced by the cytokine milieu but also by their metabolic state, cues from the microbiota and the tissue they reside in. A comprehensive understanding how these various stimuli contribute to T helper cell differentiation and phenotype could potentially provide novel ways for therapeutic intervention in autoimmunity and tissue inflammation.
    DOI:  https://doi.org/10.1016/j.coi.2020.09.001
  3. Cancers (Basel). 2020 Oct 12. pii: E2940. [Epub ahead of print]12(10):
    Manipulation of Glucose Availability to Boost Cancer Immunotherapies.
    Federica Marchesi, Debora Vignali, Beatrice Manini, Alessandra Rigamonti, Paolo Monti.
      The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies.
    Keywords:  Glut1; T cells; glucose metabolism; immune therapies
    DOI:  https://doi.org/10.3390/cancers12102940
  4. J Exp Med. 2021 Jan 04. pii: e20182232. [Epub ahead of print]218(1):
    PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance.
    Catherine L Tan, Juhi R Kuchroo, Peter T Sage, Dan Liang, Loise M Francisco, Jessica Buck, Youg Raj Thaker, Qianxia Zhang, Shannon L McArdel, Vikram R Juneja, Sun Jung Lee, Scott B Lovitch, Christine Lian, George F Murphy, Bruce R Blazar, Dario A A Vignali, Gordon J Freeman, Arlene H Sharpe.
      Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1-deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1-deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K-AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1-deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.
    DOI:  https://doi.org/10.1084/jem.20182232
  5. Mech Ageing Dev. 2020 Oct 10. pii: S0047-6374(20)30178-0. [Epub ahead of print] 111382
    Autophagy and Heat-Shock Response Impair Stress Granule Assembly during Cellular Senescence.
    Amr Omer, Devang Patel, Julian Lucas Moran, Xian Jin Lian, Sergio Di Marco, Imed-Eddine Gallouzi.
      Stress granules (SGs) are membraneless organelles formed in response to insult. These granules are related to pathological granules found in age-related neurogenerative diseases such as Parkinson's and Alzheimer's. Previously, we demonstrated that senescent cells, which accumulate with age, exposed to chronic oxidative stress, are unable to form SGs. Here, we show that the inability of senescent cells to form SGs correlates with an upregulation in both the heat-shock response and autophagy pathways, both of which are well-established promoters of SG disassembly. Our data also reveals that the knockdown of HSP70 and ATG5, important components of the heat-shock response and autophagy pathways, respectively, restores the number of SGs formed in senescent cells exposed to chronic oxidative stress. Surprisingly, under these conditions, the depletion of HSP70 or ATG5 did not affect the clearance of these SGs during their recovery from chronic stress. These data reveal that senescent cells possess a unique heat-shock and autophagy-dependent ability to impair the formation of SGs in response to chronic stress, thereby expanding the existing understanding of SG dynamics in senescent cells and their potential contribution to age-related neurodegenerative diseases.
    Keywords:  Ageing; Cellular Senescence; Molecular Biology; Oxidative Stress; Stress Granules
    DOI:  https://doi.org/10.1016/j.mad.2020.111382
  6. Immunity. 2020 Oct 13. pii: S1074-7613(20)30400-3. [Epub ahead of print]53(4): 824-839.e10
    Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.
    Marianne Weulersse, Assia Asrir, Andrea C Pichler, Lea Lemaitre, Matthias Braun, Nadège Carrié, Marie-Véronique Joubert, Marie Le Moine, Laura Do Souto, Guillaume Gaud, Indrajit Das, Elisa Brauns, Clara M Scarlata, Elena Morandi, Ashmitha Sundarrajan, Marine Cuisinier, Laure Buisson, Sabrina Maheo, Sahar Kassem, Arantxa Agesta, Michaël Pérès, Els Verhoeyen, Alejandra Martinez, Julien Mazieres, Loïc Dupré, Thomas Gossye, Vera Pancaldi, Camille Guillerey, Maha Ayyoub, Anne S Dejean, Abdelhadi Saoudi, Stanislas Goriely, Hervé Avet-Loiseau, Tobias Bald, Mark J Smyth, Ludovic Martinet.
      CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.
    Keywords:  CD226 (DNAM-1); CD8(+) T lymphocytes; Eomesodermin (Eomes); T cell exhaustion; TCR signaling; co-stimulation; immune checkpoint blockade; immunotherapy; lymphocyte function-associated antigen 1 (LFA-1); tumor immune escape
    DOI:  https://doi.org/10.1016/j.immuni.2020.09.006
  7. Cell Death Dis. 2020 Oct 14. 11(10): 854
    Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche.
    Xiaohong Peng, Yi Wu, Uilke Brouwer, Thijmen van Vliet, Boshi Wang, Marco Demaria, Lara Barazzuol, Rob P Coppes.
      Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.
    DOI:  https://doi.org/10.1038/s41419-020-03074-9
  8. Nat Immunol. 2020 Oct 12.
    Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans.
    Giovanni Galletti, Gabriele De Simone, Emilia M C Mazza, Simone Puccio, Claudia Mezzanotte, Timothy M Bi, Alexey N Davydov, Maria Metsger, Eloise Scamardella, Giorgia Alvisi, Federica De Paoli, Veronica Zanon, Alice Scarpa, Barbara Camisa, Federico S Colombo, Achille Anselmo, Clelia Peano, Sara Polletti, Domenico Mavilio, Luca Gattinoni, Shannon K Boi, Benjamin A Youngblood, Rhiannon E Jones, Duncan M Baird, Emma Gostick, Sian Llewellyn-Lacey, Kristin Ladell, David A Price, Dmitriy M Chudakov, Evan W Newell, Monica Casucci, Enrico Lugli.
      T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.
    DOI:  https://doi.org/10.1038/s41590-020-0791-5
  9. Arterioscler Thromb Vasc Biol. 2020 Oct 15. ATVBAHA120315106
    Naive CD8+ T Cells Expressing CD95 Increase Human Cardiovascular Disease Severity.
    Lindsey E Padgett, Huy Q Dinh, Runpei Wu, Dalia E Gaddis, Daniel J Araujo, Holger Winkels, Anh Nguyen, Coleen A McNamara, Catherine C Hedrick.
       OBJECTIVE: Cardiovascular disease (CVD) remains a significant global health concern with a high degree of mortality. While CD4+ T cells have been extensively studied in CVD, the importance of CD8+ T cells in this disease, despite their abundance and increased activation in human atherosclerotic plaques, remains largely unknown. To compare the peripheral T-cell signatures between humans with a high (severe) risk of CVD (including myocardial infarction or stroke) to those with a low risk of CVD. Approach and Results: Using mass cytometry, we uncovered a naive CD8+ T (TN) cell population expressing CD95 (termed CD95+CD8+ stem cell memory T [CD8 TSCM] cells) that was enriched in patients with high compared with low CVD. This T-cell subset enrichment within individuals with high CVD was a relative increase and resulted from the loss of CD95lo cells within the TN compartment. We found that CD8 TSCM cells positively correlated with CVD risk in humans, while CD8+ TN cells were inversely correlated. Atherosclerotic apolipoprotein E-deficient (ApoE-/-) mice also displayed respective 7- and 2-fold increases in CD8+ TSCM frequencies within the peripheral blood and aorta-draining paraaortic lymph nodes compared with C57BL/6J mice. CD8+ TSCM cells were 1.7-fold increased in aortas from western diet fed ApoE-/- mice compared with normal laboratory diet-fed ApoE-/- mice. Importantly, transfer of TSCM cells into immune-deficient Rag.Ldlr recipient mice that lacked T cells increased atherosclerosis, illustrating the importance of these cells in atherogenesis.
    CONCLUSIONS: CD8+ TSCM cells are increased in humans with high CVD. As these TSCM cells promote atherosclerosis, targeting them may attenuate atherosclerotic plaque progression.
    Keywords:  T lymphocytes; atherosclerosis; cardiovascular diseases; mortality; myocardial infarction
    DOI:  https://doi.org/10.1161/ATVBAHA.120.315106
  10. Front Biosci (Landmark Ed). 2021 Jan 01. 26 50-96
    Signaling pathways and effectors of aging.
    Siamak Tabibzadeh.
      Aging leads to and is associated with aberrant function of multiple signaling pathways and a host of factors that maintain cellular health. Under normal conditions, the prolongevity, 5' AMP-activated protein kinase (AMPK), is dedicated to the homeostasis of metabolism and autophagy for removal of damaged cellular compartments and molecules. A host of sirtuin family of molecules, that extend life-span, regulate metabolism and repair DNA damage, and possess either mono-ADP-ribosyltransferase, or deacylase activity. Another group of pro-longevity factors, include FOX (forkhead box) proteins, a family of transcription factors that regulate the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), a requisite step for production of NAD+, which is known to increase longevity. Loss of Klotho, a transmembrane enzyme that controls the sensitivity of the organism to insulin and suppresses oxidative stress and inflammation, leads to premature aging in mice. Hydrogen sulfide and transsulfuration pathways are crucial to the long life and are required in protection of cells against damage. Aging also leads to the imbalanced activation of other pathways and factors including p53, insulin and IGF signaling, P13K/AKT, mTOR, PKA, RAS, RTK, MEK, ERK, MAPK, CRTC-1/CREB and NFkB. Such aberrant cellular functions, disturb cell metabolism, derail autophagy and other housekeeping actions, inhibit cell division, induce inflammaging and immunosenecence, cause stem cell exhaustion and induce either senescence, apoptosis or cancer.
  11. Int J Mol Sci. 2020 Oct 10. pii: E7467. [Epub ahead of print]21(20):
    Differences in Mitochondrial Membrane Potential Identify Distinct Populations of Human Cardiac Mesenchymal Progenitor Cells.
    Elisa Gambini, Ilenia Martinelli, Ilaria Stadiotti, Maria Cristina Vinci, Alessandro Scopece, Luana Eramo, Elena Sommariva, Jessica Resta, Sabrina Benaouadi, Elisa Cogliati, Adolfo Paolin, Angelo Parini, Giulio Pompilio, Frederique Savagner.
      Adult human cardiac mesenchymal progenitor cells (hCmPC) are multipotent resident populations involved in cardiac homeostasis and heart repair. Even if the mechanisms have not yet been fully elucidated, the stem cell differentiation is guided by the mitochondrial metabolism; however, mitochondrial approaches to identify hCmPC with enhanced stemness and/or differentiation capability for cellular therapy are not established. Here we demonstrated that hCmPCs sorted for low and high mitochondrial membrane potential (using a lipophilic cationic dye tetramethylrhodamine methyl ester, TMRM), presented differences in energy metabolism from preferential glycolysis to oxidative rates. TMRM-high cells are highly efficient in terms of oxygen consumption rate, basal and maximal respiration, and spare respiratory capacity compared to TMRM-low cells. TMRM-high cells showed characteristics of pre-committed cells and were associated with higher in vitro differentiation capacity through endothelial, cardiac-like, and, to a lesser extent, adipogenic and chondro/osteogenic cell lineage, when compared with TMRM-low cells. Conversely, TMRM-low showed higher self-renewal potential. To conclude, we identified two hCmPC populations with different metabolic profile, stemness maturity, and differentiation potential. Our findings suggest that metabolic sorting can isolate cells with higher regenerative capacity and/or long-term survival. This metabolism-based strategy to select cells may be broadly applicable to therapies.
    Keywords:  TMRM; cardiac mesenchymal progenitor cells; cell fate; differentiation; metabolism; mitochondrial membrane potential
    DOI:  https://doi.org/10.3390/ijms21207467
  12. Nat Commun. 2020 Oct 16. 11(1): 5225
    Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.
    Julia Böhme, Nuria Martinez, Shamin Li, Andrea Lee, Mardiana Marzuki, Anteneh Mehari Tizazu, David Ackart, Jessica Haugen Frenkel, Alexandra Todd, Ekta Lachmandas, Josephine Lum, Foo Shihui, Tze Pin Ng, Bernett Lee, Anis Larbi, Mihai G Netea, Randall Basaraba, Reinout van Crevel, Evan Newell, Hardy Kornfeld, Amit Singhal.
      Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3-/- mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.
    DOI:  https://doi.org/10.1038/s41467-020-19095-z
  13. Hepatology. 2020 Oct 14.
    CAR-T cells as senolytic and antifibrotic therapy.
    Aashreya Ravichandra, Aveline Filliol, Robert F Schwabe.
      During chronic liver injury, hepatic stellate cells (HSC) differentiate from lipid-storing pericytes into extracellular matrix (ECM)-producing fibroblasts. While we tend to view these activated HSC as a homogenous fibrogenic cell population that accumulates in the fibrotic liver, this oversimplifies the dynamic nature of fibrogenesis, the different functional states of HSC and their ultimate fate. In parallel to their activation, HSC also undergo massive expansion under stimulation of cytokines such as platelet-derived growth factor beta, leading to their accumulation within fibrotic septa and ultimately HSC senescence. In a recent paper published in Nature, Amor et al. establish chimeric antigen receptor (CAR) T cells as new and powerful method for clearing senescent-cells and demonstrate that removal of senescent HSC ameliorates liver fibrosis (1).
    DOI:  https://doi.org/10.1002/hep.31596
  14. Blood Adv. 2020 Oct 13. 4(19): 4980
    Naive T-cell depletion in stem cell transplantation.
    Marie Bleakley.
      Allogeneic hematopoietic stem cell transplantation (HCT) is curative in many patients with advanced hematopoietic malignancies. Donor T cells not only facilitate engraftment and protect against opportunistic pathogens and residual disease, but can also cause graft-versus-host disease (GVHD), with significant morbidity and mortality. Complete T-cell depletion can not only substantially reduce GVHD rates but can also delay immune reconstitution and increase rates of opportunistic infections and relapse. Murine models have shown that naive T cells (TNs) consistently cause severe GVHD, whereas memory T cells cause milder or no GVHD and have critical graft-versus-tumor function. Informed by experiments performed in murine models of HCT, clinical trials are being conducted to evaluate TN-depleted peripheral blood stem cell (PBSC) grafts. These trials are showing very low rates of chronic GVHD and of serious acute GVHD in the HLA-matched HCT setting, with lower frequencies of opportunistic infections than after fully T-cell-depleted HCT and no apparent increase in relapse rates. Randomized clinical trials are ongoing, comparing standard unselected HCT with TN-depleted PBSCs and other promising GVHD-reduction strategies. Correlative laboratory studies will clarify how antitumor function is retained in TN-depleted HCT and inform strategies to further augment graft-versus-leukemia in patients at a high risk of relapse. TN depletion of donor lymphocyte infusions and of haploidentical stem cell grafts is also being investigated.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001888
  15. Eur J Immunol. 2020 Oct 16.
    'Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity.
    Sanne C Lith, Bram W van Os, Tom T P Seijkens, Carlie J M de Vries.
      The nuclear receptor Nur77 is expressed in a multitude of tissues, regulating cell differentiation and homeostasis. Dysregulation of Nur77 signaling is associated with cancer, cardiovascular disease, and disorders of the central nervous system. The role of Nur77 in T cells has been studied for almost 30 years now. There is a clear appreciation that Nur77 is crucial for apoptosis of self-reactive T cells. However, the regulation and function of Nur77 in mature T cells remains largely unclear. In an exciting development, Nur77 has been recently demonstrated to impinge on cancer immunotherapy involving chimeric antigen receptor (CAR) T cells and tumor infiltrating lymphocytes (TILs). These studies indicated that Nur77 deficiency reduced T cell tolerance and exhaustion, thus raising the effectiveness of immune therapy in mice. Based on these novel insights, it may be proposed that regulation of Nur77 activity holds promise for innovative drug development in the field of cellular immunotherapy in cancer. In this review we therefore summarize the role of Nur77 in T cell selection and maturation; and further develop the idea of targeting its activity in these cells as a potential strategy to augment current cancer immunotherapy treatments. This article is protected by copyright. All rights reserved.
    Keywords:  NR4A1; Nuclear receptor; T cell tolerance; immunotherapy; thymocyte selection
    DOI:  https://doi.org/10.1002/eji.202048869
  16. Biomed J. 2020 Jul 26. pii: S2319-4170(20)30126-8. [Epub ahead of print]
    Immunotherapy in older patients with cancer.
    C Granier, A Gey, S Roncelin, L Weiss, E Paillaud, E Tartour.
      Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated CD4 and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.
    Keywords:  Ageing; Cancer; Elderly; Immunosenescence; Immunotherapy; Old people; Oncogeriatry
    DOI:  https://doi.org/10.1016/j.bj.2020.07.009
  17. Biochem Pharmacol. 2020 Oct 12. pii: S0006-2952(20)30518-9. [Epub ahead of print] 114282
    Therapeutic potential of targeting mitochondrial dynamics in cancer.
    Tiago Rodrigues, Letícia Silva Ferraz.
      In the past mitochondria were considered as the "powerhouse" of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.
    Keywords:  Bioenergetics; Cancer; Cell death; Chemotherapy; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.bcp.2020.114282
  18. Aging Cell. 2020 Oct 17. e13261
    Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling.
    Chhanda Bose, Ines Alves, Preeti Singh, Philip T Palade, Eugenia Carvalho, Elisabet Børsheim, Se-Ran Jun, Amrita Cheema, Marjan Boerma, Sanjay Awasthi, Sharda P Singh.
      Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group. In the old mice, SFN restored Nrf2 activity, mitochondrial function, cardiac function, exercise capacity, glucose tolerance, and activation/differentiation of skeletal muscle satellite cells. Our results suggest that the age-associated decline in Nrf2 signaling activity and the associated mitochondrial dysfunction might be implicated in the development of age-related disease processes. Therefore, the restoration of Nrf2 activity and endogenous cytoprotective mechanisms by SFN may be a safe and effective strategy to protect against muscle and heart dysfunction due to aging.
    Keywords:  Nrf2; Oxidative stress; Sulforaphane; cardiac functions; mitochondrial dysfunction; sarcopenia
    DOI:  https://doi.org/10.1111/acel.13261
  19. Dev Comp Immunol. 2020 Oct 07. pii: S0145-305X(20)30436-5. [Epub ahead of print] 103881
    Non-canonical roles of NAMPT and PARP in inflammation.
    Francisco J Martínez-Morcillo, Joaquín Cantón-Sandoval, Teresa Martínez-Menchón, Raúl Corbalán-Vélez, Pablo Mesa-Del-Castillo, Ana B Pérez-Oliva, Diana García-Moreno, Victoriano Mulero.
      Nicotinamide adenine dinucleotide (NAD+) is the most important hydrogen carrier in cell redox reactions. It is involved in mitochondrial function and metabolism, circadian rhythm, the immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin remodeling and epigenetics. Recently, NAD+ has been recognized as the molecule of life, since, by increasing NAD+ levels in old or sick animals, it is possible to improve their health and lengthen their lifespan. In this review, we summarize the contribution of NAD+ metabolism to inflammation, with special emphasis in the major NAD+ biosynthetic enzyme, nicotinamide phosphoribosyl transferase (NAMPT), and the NAD+-consuming enzyme, poly(ADP-ribose) polymerase (PARP). The extracurricular roles of these enzymes, i.e. the proinflammatory role of NAMPT after its release, and the ability of PARP to promote a novel form of cell death, known as parthanatos, upon hyperactivation are revised and discussed in the context of several chronic inflammatory diseases.
    Keywords:  NAD(+); NAMPT; PARP; chronic inflammation; immunity; parthanatos
    DOI:  https://doi.org/10.1016/j.dci.2020.103881
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