bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒12‒05
eleven papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Blood. 2021 Dec 03. pii: blood.2021012714. [Epub ahead of print]
      Adoptive cancer immunotherapy can induce objective clinical efficacy in patients with advanced cancer; however, a sustained response is achieved in a minority of cases. The persistence of infused T cells is an essential determinant of a durable therapeutic response. Antitumor T cells undergo a genome-wide remodeling of the epigenetic architecture upon repeated antigen encounters, which inevitably induces progressive T-cell differentiation and the loss of longevity. In this study, we identified PR domain zinc finger protein 1 (PRDM1) i.e., Blimp-1, as a key epigenetic gene associated with terminal T-cell differentiation. The genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion in repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells. PRDM1 disruption promoted the expansion of less differentiated memory CAR-T cells in vivo, which enhanced T-cell persistence and improved therapeutic efficacy in multiple tumor models. Mechanistically, PRDM1-ablated T cells displayed enhanced chromatin accessibility of the genes that regulate memory formation, thereby leading to the acquisition of gene expression profiles representative of early memory T cells. PRDM1 knockout also facilitated maintaining an early memory phenotype and cytokine polyfunctionality in T-cell receptor-engineered T cells as well as tumor-infiltrating lymphocytes. In other words, targeting PRDM1 enabled the generation of superior antitumor T cells, which is potentially applicable to a wide range of adoptive cancer immunotherapies.
  2. Cancer Treat Res Commun. 2021 Nov 20. pii: S2468-2942(21)00190-8. [Epub ahead of print]29 100494
      Multiple myeloma (MM) is a disease of the elderly. Changes that occur in the immune system with aging, also known as immunosenescence, have been associated with decreased tumor immunosurveillance and are thought to contribute to the development of MM and other cancers in the elderly. Once MM establishes itself in the bone marrow, immunosenescence related changes have been observed in the immune tumor microenvironment (iTME) and are driven by the malignant cells. The efficacy of novel immunotherapies used to treat MM has been blunted by detrimental iTME changes that occur at later disease stages and are, to some extent, driven by prior therapies. In this review, we discuss general changes that occur in the immune system with aging as well as our current knowledge of immunosenescence in MM. We discuss the differences and overlap between T cell senescence and exhaustion as well as potential methods to prevent or reverse immunosenescence. We focus predominantly on T cell immunosenescence which has been better evaluated in this disease and is more pertinent to novel MM immunotherapies. Our lack of understanding of the drivers of immunosenescence at each stage of the disease, from precursor stages to heavily pretreated MM, represents a major barrier to improving the efficacy of novel and existing therapies.
    Keywords:  Immune microenvironment; Immunosenescence; Inflammaging; Myeloma
  3. Bull Exp Biol Med. 2021 Dec;172(2): 169-174
      We studied the effects of pregnancy-specific β1-glycoprotein (PSG) on the replicative potential of naïve T cells (CD45RA+) and immune memory T cells (CD45R0+) in vitro by evaluating the expression of the hTERT gene in combination with the proliferative activity of cells. Human PSG was obtained by the author's patented method of immunopurification using a biospecific sorbent with subsequent removal of immunoglobulin contamination on a HiTrap Protein G HP column. We used monocultures of CD45RA+ and CD45R0+ lymphocytes isolated from peripheral blood mononuclear cells of reproductive-age women. It was found that PSG in physiological concentrations inhibited the expression of the hTERT gene mRNA in naïve T cells and immune memory T cells and simultaneously reduced the number of proliferating T cells estimated by the differential gating method. At the same time, PSG reduced CD71 expression only on naïve T cells without affecting this molecule on immune memory T cells. Thus, PSG decreased the replication potential and suppressed the proliferation of T cells and immune memory T cells, which in the context of pregnancy can contribute to the formation of immune tolerance to the semi-allogeneic embryo.
    Keywords:  hTERT; memory T cells; naïve T cells; pregnancy-specific β1-glycoprotein; proliferation
  4. Nat Rev Drug Discov. 2021 Dec 03.
      One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.
  5. Brain. 2021 Nov 29. 144(10): 3126-3141
      Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.
    Keywords:  T-cell; antioxidative T-cell capacities; autoimmunity; dimethyl fumarate; multiple sclerosis;  metabolism
  6. Nat Aging. 2021 Oct;1(10): 870-879
      Cellular senescence represents a distinct cell fate characterized by replicative arrest in response to a host of extrinsic and intrinsic stresses. Senescence provides programming during development and wound healing, while limiting tumorigenesis. However, pathologic accumulation of senescent cells is implicated in a range of diseases and age-associated morbidities across organ systems. Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting deleterious systemic effects. Senescent cell removal by apoptosis-inducing "senolytic" agents or therapies that inhibit the senescence-associated secretory phenotype, SASP inhibitors, have demonstrated benefit in both pre-clinical and clinical models of geriatric decline and chronic diseases, suggesting senescent cells represent a pharmacologic target for alleviating effects of fundamental aging processes. However, senescent cell populations are heterogeneous in form, function, tissue distribution, and even differ among species, possibly explaining issues of bench-to-bedside translation in current clinical trials. Here, we review features of senescent cells and strategies for targeting them, including immunologic approaches, as well as key intracellular signaling pathways. Additionally, we survey current senolytic therapies in human trials. Collectively, there is demand for research to develop targeted senotherapeutics that address the needs of the aging and chronically-ill.
  7. J Genet Genomics. 2021 Nov 29. pii: S1673-8527(21)00358-1. [Epub ahead of print]
      Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Of the multiple signaling pathways that regulate metabolism, such as PI3K/AKT, mTOR, AMPK, and sirtuins, mammalian sirtuins also play unique roles in aging. By understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will focus on canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and oxidative stress, calorie restriction and disease.
    Keywords:  Metabolism and aging regulation; Mitochondrial sirtuins; SIRT3; SIRT4; SIRT5; age-related diseases
  8. Curr Mol Med. 2021 Nov 28.
      Skeletal muscles must generate and distribute energy properly in order to function perfectly. Mitochondria in skeletal muscle cells form vast networks to meet this need, and their functions may improve as a result of exercise. In the present review, we discussed exercise-induced mitochondrial adaptations, age-related mitochondrial decline, and a biomarker as a mitochondrial function indicator and exercise interference.
    Keywords:  Skeletal muscle; aging; biomarker; endurance exercise; mitochondrial activity; strength training
  9. Nutr Res Pract. 2021 Dec;15(6): 673-685
      BACKGROUND/OBJECTIVES: Obesity is associated with the impaired regulation of T cells characterized by increased numbers of Th1 and Th17 cells and the dysregulation of vitamin D metabolism. Both obesity and vitamin D have been reported to affect autophagy; however, a limited number of studies have investigated the effects of vitamin D on T cell autophagy in obese mice. Therefore, we aimed to determine whether in vitro treatment with vitamin D affects the proliferation, function, and autophagy of T cells from obese and control mice.MATERIALS/METHODS: Five-week-old male C57BL/6 mice were fed control or high-fat diets (10% or 45% kcal fat: CON or HFDs, respectively) for 12 weeks. Purified T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either 10 nM 1,25(OH)2D3 or 0.1% ethanol (vehicle control). The proliferative response; expression of CD25, Foxp3, RORγt, and autophagy-related proteins (LC3A/B, SQSTM1/P62, BECLIN-1, ATG12); and the production of interferon (IFN)-γ, interleukin (IL)-4, IL-17A, and IL-10 by T cells were measured.
    RESULTS: Compared with the CON group, T cell proliferation tended to be lower, and the production of IFN-γ was higher in the HFD group. IL-17A production was reduced by 1,25(OH)2D3 treatment in both groups. The LC3 II/I ratio was higher in the HFD group than the CON group, but P62 did not differ. We observed no effect of vitamin D treatment on T cell autophagy.
    CONCLUSIONS: Our findings suggest that diet-induced obesity may impair the function and inhibit autophagy of T cells, possibly leading to the dysregulation of T cell homeostasis, which may be behind the aggravation of inflammation commonly observed in obesity.
    Keywords:  Obesity; T lymphocytes; autophagy; vitamin D
  10. Naunyn Schmiedebergs Arch Pharmacol. 2021 Dec 01.
      Macrophages are myeloid immune cells, present in virtually all tissues which exhibit considerable functional plasticity and diversity. Macrophages are often subdivided into two distinct subsets described as classically activated (M1) and alternatively activated (M2) macrophages. It has recently emerged that metabolites regulate the polarization and function of macrophages by altering metabolic pathways. These metabolites often cannot freely pass the cell membrane and are therefore transported by the corresponding metabolite transporters. Here, we reviewed how glucose, glutamate, lactate, fatty acid, and amino acid transporters are involved in the regulation of macrophage polarization. Understanding the interactions among metabolites, metabolite transporters, and macrophage function under physiological and pathological conditions may provide further insights for novel drug targets for the treatment of macrophage-associated diseases. In Brief Recent studies have shown that the polarization and function of macrophages are regulated by metabolites, most of which cannot pass freely through biofilms. Therefore, metabolite transporters required for the uptake of metabolites have emerged seen as important regulators of macrophage polarization and may represent novel drug targets for the treatment of macrophage-associated diseases. Here, we summarize the role of metabolite transporters as regulators of macrophage polarization.
    Keywords:  Macrophage polarization; Metabolite transporters; Metabolites; Solute carriers