bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒10‒25
twenty-one papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. PD-1 Expression on CD8+CD28- T cells within inflammatory synovium is associated with Relapse: A cohort of Rheumatoid Arthritis.
  2. Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function.
  3. Metabolite Transporters as Regulators of Immunity.
  4. Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial.
  5. FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.
  6. Translational control during cellular senescence.
  7. Hepatic and splenic immune response during acute vs. chronic Brucella melitensis infection using in situ microscopy.
  8. Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey.
  9. TRPM8 channel augments T cell activation and proliferation.
  10. Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens.
  11. T cell regeneration after immunological injury.
  12. Overcoming T cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.
  13. Alterations of Specific Lymphocytic Subsets with Aging and Age-Related Metabolic and Cardiovascular Diseases.
  14. Revisiting T Cell Tolerance as a Checkpoint Target for Cancer Immunotherapy.
  15. Quality control of the mitochondrial proteome.
  16. Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies.
  17. Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.
  18. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
  19. TGF-β suppresses type 2 immunity to cancer.
  20. Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease.
  21. Tumor fibroblast-derived FGF2 regulates expression of SPRY1 in esophageal tumor-infiltrating T cells and plays a role in T cell exhaustion.
  1. Immunol Lett. 2020 Oct 15. pii: S0165-2478(20)30401-6. [Epub ahead of print]228 76-82
    PD-1 Expression on CD8+CD28- T cells within inflammatory synovium is associated with Relapse: A cohort of Rheumatoid Arthritis.
    Faezeh Ajam, Mehrdad Aghaei, Saeed Mohammadi, Hadiseh Samiei, Nasser Behnampour, Ali Memarian.
      Defect in T lymphocyte homeostasis could implicate initiation and development of rheumatoid arthritis (RA). Since PD-1 plays a key role in the regulation of T lymphocytes, its expression pattern in various CD8+ T cell subsets could be so effective in RA pathogenesis. Here, we investigated the expression of PD-1 and CXCR3 on CD8+CD28- T cells in association with the IFN-γ levels in patients with RA. A total of 42 RA patients, including 10 newly-diagnosed (ND) and 32 relapsed (RL) cases and also 20 healthy donors were enrolled. Phenotypic characterization of CD8+ T cells derived from peripheral blood (PB) and synovial fluid (SF) was performed by flow cytometry. The plasma and SF IFN-γ levels were also assessed by ELISA. The frequency of CD8+CD28- T cells showed no significant differences between patients and controls while its higher levels were observed in PB, versus SF of RL patients. Relapsed patients also showed higher CXCR3 and especially PD-1 expression on their CD8+CD28- T cells. The IFN-γ concentration was elevated in SF of ND patients while its plasma level was significantly lower in RL subgroup than controls. Although PD-1 could induce immune suppression in effector T cells, it is upregulated during inflammation and its overexpression on CD8+CD28- T cells within inflammatory synovium is associated with severity of disease in our cohort of RA patients.
    Keywords:  CD8+ T-cells; CXCR3; Immunophenotype; PD-1; Relapse; Rheumatoid Arthritis
    DOI:  https://doi.org/10.1016/j.imlet.2020.10.005
  2. Cell Stem Cell. 2020 Oct 10. pii: S1934-5909(20)30493-8. [Epub ahead of print]
    Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function.
    Els Mansell, Valgardur Sigurdsson, Elitza Deltcheva, John Brown, Chela James, Kenichi Miharada, Shamit Soneji, Jonas Larsson, Tariq Enver.
      Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
    Keywords:  Aging; Hematopoietc Stem Cell; Lineage bias; Mitochondria; Mitochondrial Membrane Potential; Mitoquinol; Transcription Rate
    DOI:  https://doi.org/10.1016/j.stem.2020.09.018
  3. Metabolites. 2020 Oct 19. pii: E418. [Epub ahead of print]10(10):
    Metabolite Transporters as Regulators of Immunity.
    Hauke J Weiss, Stefano Angiari.
      In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations.
    Keywords:  T cells; cell metabolism; immunity; macrophages; metabolite transporter; solute carrier
    DOI:  https://doi.org/10.3390/metabo10100418
  4. J Gerontol A Biol Sci Med Sci. 2020 Oct 18. pii: glaa271. [Epub ahead of print]
    Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial.
    Glenn Choon Lim Wong, Ted Kheng Siang Ng, Jia Le Lee, Pei Yi Lim, Sean Kai Jie Chua, Crystal Tan, Michelle Chua, Janice Tan, Samantha Lee, Angelia Sia, Maxel K W Ng, Rathi Mahendran, Ee Heok Kua, Roger C M Ho, Anis Larbi.
      BACKGROUND: With the challenges that aging populations pose to healthcare, interventions that facilitate alleviation of age-related morbidities are imperative. A prominent risk factor for developing age-related morbidities is immunosenescence, characterized by increased chronic low-grade inflammation, resulting in T-cell exhaustion and senescence. Contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in the form of Horticultural Therapy (HT). We aimed to examine the effects of HT on immunosenescence.METHODS: We conducted a randomized controlled trial with 59 older adults assigned to either the HT intervention or waitlist control group. Older adults in the HT intervention group underwent HT intervention program over six months. Venous blood was drawn at baseline and at the 3 rd and 6 th month from the commencement of this study. For participants who attended all three blood collection time points (HT: n=22, waitlist: n=24), flow cytometry analysis was performed on whole blood samples to evaluate the kinetics of lymphocyte subsets over the intervention period, revealing the composition of CD4+ and CD8+ subsets expressing exhaustion markers - CD57, CTLA4, and KLRG1. Enzyme-linked immunosorbent assays were employed to measure changes in plasma IL-6 levels.
    RESULTS: HT is associated with increased numbers of naïve CD8+ T cells and fewer CTLA4-expressing terminally differentiated effector CD4+ and CD8+ memory T cells re-expressing CD45RA (TEMRA). Furthermore, IL-6 levels were reduced during HT, and the frequencies of naive and TEMRA CD8+ T cells were found to be associated with IL-6 levels.
    CONCLUSION: HT is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammaging in older adults. The positive effects of HT on T-cell exhaustionwere associated with the reduction of IL-6 levels.
    Keywords:  CTLA-4; Geroscience; IL-6; Immunosenescence; Inflammaging
    DOI:  https://doi.org/10.1093/gerona/glaa271
  5. Cell Metab. 2020 Oct 14. pii: S1550-4131(20)30537-4. [Epub ahead of print]
    FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.
    Lihui Wang, Ruping Chen, Guo Li, Zhiguo Wang, Jun Liu, Ying Liang, Jun-Ping Liu.
      Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.
    Keywords:  DNA damage response; FBXW7; TPP1; cellular senescence; chronic stress; idiopathic pulmonary fibrosis; premature aging; proteostasis; stem cells; telomere; telomere uncapping
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.004
  6. Mol Cell Biol. 2020 Oct 19. pii: MCB.00512-20. [Epub ahead of print]
    Translational control during cellular senescence.
    Matthew J Payea, Carlos Anerillas, Ravi Tharakan, Myriam Gorospe.
      Senescence is a state of long-term cell-cycle arrest that arises in cells that have incurred sub-lethal damage. While senescent cells no longer replicate, they remain metabolically active and further develop unique and stable phenotypes that are not present in proliferating cells. On one hand, senescent cells increase in size, maintain an active mTORC1 complex, and produce and secrete a substantial amount of inflammatory proteins as part of the senescence associated secretory phenotype (SASP). On the other hand, these pro-growth phenotypes contrast with the p53-mediated growth arrest typical of senescent cells that is associated with nucleolar stress and an inhibition of rRNA processing and ribosome biogenesis. In sum, translation in senescent cells paradoxically comprises both a global repression of translation triggered by DNA damage and a select increase in the translation of specific proteins, including SASP factors.
    DOI:  https://doi.org/10.1128/MCB.00512-20
  7. Comp Immunol Microbiol Infect Dis. 2020 Oct 02. pii: S0147-9571(20)30079-5. [Epub ahead of print]73 101490
    Hepatic and splenic immune response during acute vs. chronic Brucella melitensis infection using in situ microscopy.
    Juliane Daggett, Alexandra Rogers, Jerome Harms, Gary A Splitter, Marina Durward-Diioia.
      Brucella melitensis is an intracellular bacteria causing disease in humans as an incidental host. The infection initiates as acute flu-like symptoms and may transform into a chronic cyclic infection. This cyclic infection may be partly due to the bacteria's ability to persist within antigen presenting cells and evade the CD8 + T cell response over long periods of time. This research aims to characterize the immune response of the acute and chronic forms of brucellosis in the murine liver and spleen. We also sought to determine if the exhaustion of the CD8 + T cells was a permanent or temporary change. This was accomplished by using adoptive transfer of acutely infected CD8 + T cells and chronically infected CD8 + T cells into a naïve host followed by re-infection. The histological examination presented supports the concept that exhausted T-cells can regain function through evidence of granulomatous inflammation after virulent challenge in a new host environment.
    Keywords:  Acute infection; Adoptive transfer; Bacterial infection; Brucella melitensis; Brucellosis; Chronic infection; Cytotoxic T cells; Granuloma; Liver; Spleen; T cell exhaustion
    DOI:  https://doi.org/10.1016/j.cimid.2020.101490
  8. Nat Rev Immunol. 2020 Oct 19.
    Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey.
    Mohamed A ElTanbouly, Randolph J Noelle.
      Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell's journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.
    DOI:  https://doi.org/10.1038/s41577-020-00454-2
  9. Cell Biol Int. 2020 Oct 14.
    TRPM8 channel augments T cell activation and proliferation.
    Tusar Kanta Acharya, Ankit Tiwari, Rakesh Kumar Majhi, Chandan Goswami.
      The Transient Receptor Potential Melastatin 8 (TRPM8) is an ion channel that has been widely studied as a cold-sensitive nociceptor. However, its importance in non-neuronal cells is mostly unexplored. Here, we describe the presence and functional significance of endogenous TRPM8, a non-selective Ca2+-channel in T cell functions. Major pool of TRPM8 resides at T cell surface and its surface accumulation significantly increases in activated T cells. TRPM8 activation synergizes with T cell receptor stimulation to increase CD25, CD69 levels and enhances secretion of proinflammatory cytokine TNF. However, TRPM8 inhibition doesn't restrict TCR stimulation mediated activation of T cells, indicating that unlike the heat-sensitive TRPV1 and TRPV4 channels, the cold-sensitive TRPM8 channel may be dispensable during T cell activation, at least in mice. In this work we demonstrate that TRPM8 promotes TCR-induced intracellular calcium increase. TRPM8 activation is beneficial for T cell activation and differentiation into effector cells. TRPM8 inhibition during T cell activation process may lead to altered phenotype and reduced proliferation, without affecting cell viability. These results collectively establish TRPM8 as a functional calcium channel whose activation may be utilized for mounting an effective immune response. The findings of this work will be relevant for the regulation and response of T cells during cell mediated immunity. These results will likely further our understanding of the role of ion channels in T cell activation. This article is protected by copyright. All rights reserved.
    Keywords:  CD3; ConA; Immunity; T cell activation; T cell proliferation; TRP channel
    DOI:  https://doi.org/10.1002/cbin.11483
  10. Cancers (Basel). 2020 Oct 19. pii: E3045. [Epub ahead of print]12(10):
    Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens.
    Morten Orebo Holmström, Mads Hald Andersen.
      The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO+ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.
    Keywords:  RAS; T cell memory; immune surveillance; immuno-editing; neo-antigens
    DOI:  https://doi.org/10.3390/cancers12103045
  11. Nat Rev Immunol. 2020 Oct 23.
    T cell regeneration after immunological injury.
    Enrico Velardi, Jennifer J Tsai, Marcel R M van den Brink.
      Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.
    DOI:  https://doi.org/10.1038/s41577-020-00457-z
  12. Blood. 2020 Oct 19. pii: blood.2020005867. [Epub ahead of print]
    Overcoming T cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.
    Amel Sengal, Jessica Velazquez, Meryl Virginia Hahne, Thomas Burke, Harshal Abhyankar, Robert William Ignacio Reyes, Walter Olea, Brooks P Scull, Olive Simone Eckstein, Camille Bigenwald, Catherine M Bollard, Wendong Yu, Miriam Merad, Kenneth L McClain, Carl E Allen, Rikhia Chakraborty.
      Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent mitogen-activated protein kinase (MAPK) pathway activation. Standard of care chemotherapy strategies is inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis and potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited 'exhausted' phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intra-lesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intra-lesional regulatory T cells (Tregs) demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses: whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cell and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment and highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1182/blood.2020005867
  13. Life (Basel). 2020 Oct 17. pii: E246. [Epub ahead of print]10(10):
    Alterations of Specific Lymphocytic Subsets with Aging and Age-Related Metabolic and Cardiovascular Diseases.
    Ying Jen Chen, Yi Jen Liao, Van Thi Ngoc Tram, Chung Hao Lin, Kuo Chen Liao, Chao Lien Liu.
      To investigate the association of immunosenescence with aged-related morbidity in the elderly, a clinical study was conducted to analyze and compare the alterations in peripheral blood (PB) T-cell subsets among young healthy (YH) controls, elderly healthy (EH) controls, and age-matched elderly patients with metabolic diseases (E-MDs), with cardiovascular diseases (E-CVDs) or with both (E-MDs/E-CVDs). The frequencies of CD3T, CD8T and invariant natural killer T (iNKT) cells were decreased in the EH, E-MD and E-CVD cohorts, indicating a decline in defense function. Although CD4T and regulatory T (Treg) cell frequencies tended to increase with aging, they were lower in patients with E-MDs and E-CVDs. Subset analyses of T-cells consistently showed the accumulation of senescent T-cell in aging and in patients with E-MDs and E-CVDs, compared with YH volunteers. These accumulated senescent T-cells were undergoing apoptosis upon stimulation due to the replicative senescence stage of T-cells. In addition, serum levels of cytokines, including interferon (IF)-γ, transforming growth factor (TGF)-β and growth differentiation factor (GDF)-15, consistently reflected alterations in T-cell subsets. This study demonstrated that T-cell subset changes with paralleled alterations in cytokines were associated with aging and age-related pathogenesis. These altered T-cell subsets and/or cytokines can potentially serve as biomarkers for the prevention, diagnosis and treatment of age-related morbidities.
    Keywords:  E-CVDs; E-MDs; TEM; TEMRA; aging; immunosenescence
    DOI:  https://doi.org/10.3390/life10100246
  14. Front Immunol. 2020 ;11 589641
    Revisiting T Cell Tolerance as a Checkpoint Target for Cancer Immunotherapy.
    Simone Nüssing, Joseph A Trapani, Ian A Parish.
      Immunotherapy has revolutionized the treatment of cancer. Nevertheless, the majority of patients do not respond to therapy, meaning a deeper understanding of tumor immune evasion strategies is required to boost treatment efficacy. The vast majority of immunotherapy studies have focused on how treatment reinvigorates exhausted CD8+ T cells within the tumor. In contrast, how therapies influence regulatory processes within the draining lymph node is less well studied. In particular, relatively little has been done to examine how tumors may exploit peripheral CD8+ T cell tolerance, an under-studied immune checkpoint that under normal circumstances prevents detrimental autoimmune disease by blocking the initiation of T cell responses. Here we review the therapeutic potential of blocking peripheral CD8+ T cell tolerance for the treatment of cancer. We first comprehensively review what has been learnt about the regulation of CD8+ T cell peripheral tolerance from the non-tumor models in which peripheral tolerance was first defined. We next consider how the tolerant state differs from other states of negative regulation, such as T cell exhaustion and senescence. Finally, we describe how tumors hijack the peripheral tolerance immune checkpoint to prevent anti-tumor immune responses, and argue that disruption of peripheral tolerance may contribute to both the anti-cancer efficacy and autoimmune side-effects of immunotherapy. Overall, we propose that a deeper understanding of peripheral tolerance will ultimately enable the development of more targeted and refined cancer immunotherapy approaches.
    Keywords:  CD8+ T cell; cancer immune evasion; cancer immunotherapies; checkpoint blockade; immunological tolerance
    DOI:  https://doi.org/10.3389/fimmu.2020.589641
  15. Nat Rev Mol Cell Biol. 2020 Oct 22.
    Quality control of the mitochondrial proteome.
    Jiyao Song, Johannes M Herrmann, Thomas Becker.
      Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.
    DOI:  https://doi.org/10.1038/s41580-020-00300-2
  16. Cell Calcium. 2020 Oct 16. pii: S0143-4160(20)30150-0. [Epub ahead of print]92 102308
    Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies.
    Ilaria Genovese, Bianca Vezzani, Alberto Danese, Lorenzo Modesti, Veronica Angela Maria Vitto, Virginia Corazzi, Stefano Pelucchi, Paolo Pinton, Carlotta Giorgi.
      As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca2+ homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca2+ signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.
    Keywords:  Ca(2+) signaling; Mitochondria; bioenergetics; cGAS-cGAMP-STING pathway; cancer; mitophagy
    DOI:  https://doi.org/10.1016/j.ceca.2020.102308
  17. Nat Metab. 2020 Oct 19.
    Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.
    Lisa Maria Koch, Eivind Salmorin Birkeland, Stefania Battaglioni, Xiao Helle, Mayura Meerang, Stefanie Hiltbrunner, Alfredo J Ibáñez, Matthias Peter, Alessandra Curioni-Fontecedro, Isabelle Opitz, Reinhard Dechant.
      Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1038/s42255-020-00297-0
  18. Proc Natl Acad Sci U S A. 2020 Oct 19. pii: 201921223. [Epub ahead of print]
    Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
    Shan Sun, Lingjie Luo, Wenhua Liang, Qian Yin, Jing Guo, Anthony M Rush, Zhibao Lv, Qiming Liang, Michael A Fischbach, Justin L Sonnenburg, Dylan Dodd, Mark M Davis, Feng Wang.
      Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10-mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.
    Keywords:  Bifidobacterium; immune checkpoint blockade; metabolism; microbiota; regulatory T cell
    DOI:  https://doi.org/10.1073/pnas.1921223117
  19. Nature. 2020 Oct 21.
    TGF-β suppresses type 2 immunity to cancer.
    Ming Liu, Fengshen Kuo, Kristelle J Capistrano, Davina Kang, Briana G Nixon, Wei Shi, Chun Chou, Mytrang H Do, Efstathios G Stamatiades, Shengyu Gao, Shun Li, Yingbei Chen, James J Hsieh, A Ari Hakimi, Ichiro Taniuchi, Timothy A Chan, Ming O Li.
      The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity1, and host-directed pathogen containment exemplified by type 2 immunity in induction of tissue repair2. Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined3-5, but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4+ T cells, but not CD8+ T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-γ (IFN-γ). Thus, type 2 immunity can be mobilized as an effective tissue-level defence mechanism against cancer.
    DOI:  https://doi.org/10.1038/s41586-020-2836-1
  20. iScience. 2020 Oct 23. 23(10): 101556
    Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease.
    José Fernández Navarro, Deborah L Croteau, Aleksandra Jurek, Zaneta Andrusivova, Beimeng Yang, Yue Wang, Benjamin Ogedegbe, Tahira Riaz, Mari Støen, Claus Desler, Lene Juel Rasmussen, Tone Tønjum, Marie-Christine Galas, Joakim Lundeberg, Vilhelm A Bohr.
      Alzheimer disease (AD) is a devastating neurological disease associated with progressive loss of mental skills and cognitive and physical functions whose etiology is not completely understood. Here, our goal was to simultaneously uncover novel and known molecular targets in the structured layers of the hippocampus and olfactory bulbs that may contribute to early hippocampal synaptic deficits and olfactory dysfunction in AD mice. Spatially resolved transcriptomics was used to identify high-confidence genes that were differentially regulated in AD mice relative to controls. A diverse set of genes that modulate stress responses and transcription were predominant in both hippocampi and olfactory bulbs. Notably, we identify Bok, implicated in mitochondrial physiology and cell death, as a spatially downregulated gene in the hippocampus of mouse and human AD brains. In summary, we provide a rich resource of spatially differentially expressed genes, which may contribute to understanding AD pathology.
    Keywords:  Cellular Neuroscience; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2020.101556
  21. Cancer Res. 2020 Oct 22. pii: canres.1542.2020. [Epub ahead of print]
    Tumor fibroblast-derived FGF2 regulates expression of SPRY1 in esophageal tumor-infiltrating T cells and plays a role in T cell exhaustion.
    Qing-Yun Chen, Yi-Ni Li, Xin-Yue Wang, Xu Zhang, Yi Hu, Lei Li, Da-Qin Suo, Ke Ni, Zhuo Li, Jia-Rong Zhan, Ting-Ting Zeng, Ying-Hui Zhu, Yan Li, Li-Jia Ma, Xin-Yuan Guan.
      T cell exhaustion was initially identified in chronic infection in mice and was subsequently described in humans with cancer. Although the distinct signature of exhausted T cells in cancer has been well investigated, the molecular mechanism of T cell exhaustion in cancer is not fully understood. Using single-cell RNA sequencing, we report here that exhausted T cells in esophageal cancer were more heterogeneous than previously clarified. SPRY1 was notably enriched in two subsets of exhausted CD8+ T cells. When overexpressed, SPRY1 impaired T cell activation by interacting with CBL, a negative regulator of ZAP-70 tyrosine phosphorylation. Data from the Tumor Immune Estimation Resource revealed a strong correlation between FGF2 and SPRY1 expression in esophageal cancer. High expression of FGF2 was evident in fibroblasts from esophageal cancer tissue and correlated with poor overall survival. In vitro administration of FGF2 significantly upregulated expression of SPRY1 in CD8+ T cells and attenuated TCR-triggered CD8+ T cell activation. A mouse tumor model confirmed that overexpression of FGF2 in fibroblasts significantly upregulated SPRY1 expression in exhausted T cells, impaired T cell cytotoxic activity, and promoted tumor growth. Thus, these findings identify FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells in esophageal cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1542
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