bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒10‒16
fifteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Metabolic and epigenetic orchestration of (CAR) T cell fate and function.
  2. Loss of immune regulation in aged T-cells: A metabolic review to show lack of ability to control responses within the self.
  3. Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.
  4. CD8+ T cell metabolic changes in breast cancer.
  5. d-2HG Inhibits Effector T Cells by Altering Metabolic Programming.
  6. Clinical implications of T cell exhaustion for cancer immunotherapy.
  7. Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.
  8. TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine.
  9. T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy.
  10. Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
  11. Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
  12. Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes.
  13. Metabolic communication in the tumour-immune microenvironment.
  14. Senescent cells in the brain and where to find them.
  15. Boosting cytotoxic T cells for immunotherapy.
  1. Cancer Lett. 2022 Oct 07. pii: S0304-3835(22)00435-9. [Epub ahead of print]550 215948
    Metabolic and epigenetic orchestration of (CAR) T cell fate and function.
    Behnia Akbari, Zahra Hosseini, Pardis Shahabinejad, Saba Ghassemi, Hamid Reza Mirzaei, Roddy S O'Connor.
      Longevity, functionality, and metabolic fitness are key determinants of chimeric antigen receptor (CAR) T cell efficacy. Activated T cells follow an ordered differentiation program which is facilitated by metabolic adaptations. In response to antigen, T cells undergo a highly-regulated shift to glycolysis. Committing to, and engaging in, glycolysis supports T cell expansion and effector function. Inside tumors, heightened tumor cell metabolism and dysregulated perfusion create a competition for nutrients. As local metabolism supports the differentiation of T cells into functionally-competent progeny, nutrient depletion coupled with persisting antigen can trigger T cell exhaustion. Emerging insights into the barriers impeding CAR T cell function in hostile tumor microenvironments (TME) reveal that metabolic intermediates shape the immune response by influencing epigenetic programs and the control of gene expression. In this review, we discuss recent progress connecting cellular metabolism with epigenetic states in CAR T cells. Given that CAR T cell metabolism can be dynamically regulated, we introduce the concepts of "metabolic-based epigenetic altering" and "epigenetic-based metabolism altering" to restore functional competence in CARTs traversing solid TMEs.
    Keywords:  CAR T cell; Epigenetics; Immunotherapy; Metabolism; T cell exhaustion
    DOI:  https://doi.org/10.1016/j.canlet.2022.215948
  2. Hum Immunol. 2022 Oct 10. pii: S0198-8859(22)00204-X. [Epub ahead of print]
    Loss of immune regulation in aged T-cells: A metabolic review to show lack of ability to control responses within the self.
    Bharat Singh, Ambak Kumar Rai.
      The progressive decline of the anatomical architecture and loss of functional integrity of an individual is aging. Accumulation of degenerative cellular and molecular changes in the aging cells increases the fragility at the cellular and molecular levels. It pushes towards age-associated diseases like Alzheimer's disease, hypertension, cancer, cardiovascular diseases, etc. The impaired T cell function in aging is a leading contributor to increased susceptibility to pathogens, minimized vaccine response, and skewed inflammation. Recent studies about the role of T cells in the remodelling of the immune system have provided ways to examine and explore aging puzzles and their correlation with T cell functions. Here we review the metabolic aspect of T cell function and its possible restoration. IL-7 and mTOR mediated pathways and their association with reactivation of effector T cell function could help understanding the dark side of the compromised adaptive immune system, particularly T cell response, in aging. Understanding these crucial fundamentals could help design and target new molecules to prevent loss of T cell functionality in aging.
    Keywords:  Aging; Immune system; Metabolism; T cells; mTOR
    DOI:  https://doi.org/10.1016/j.humimm.2022.10.002
  3. Cells. 2022 Oct 01. pii: 3103. [Epub ahead of print]11(19):
    Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.
    Yu Ping, Chunyi Shen, Bo Huang, Yi Zhang.
      T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
    Keywords:  T cell; T cell metabolism; anti-tumor function; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells11193103
  4. Biochim Biophys Acta Mol Basis Dis. 2022 Oct 08. pii: S0925-4439(22)00236-8. [Epub ahead of print] 166565
    CD8+ T cell metabolic changes in breast cancer.
    Angela Castoldi, Jennifer Lee, Daniel de Siqueira Carvalho, Fabrício O Souto.
      Immunometabolism has advanced our understanding of how the cellular environment and nutrient availability regulates immune cell fate. Not only are metabolic pathways closely tied to cell signaling and differentiation, but can induce different subsets of immune cells to adopt unique metabolic programs, influencing disease progression. Dysregulation of immune cell metabolism plays an essential role in the progression of several diseases including breast cancer (BC). Metabolic reprogramming plays a critical role in regulating T cell functions. CD8+ T cells are an essential cell type within the tumor microenvironment (TME). To induce antitumor responses, CD8+ T cells need to adapt their metabolism to fulfill their energy requirement for effective function. However, different markers and immunologic techniques have made identifying specific CD8+ T cells subtypes in BC a challenge to the field. This review discusses the immunometabolic processes of CD8+ T cell in the TME in the context of BC and highlights the role of CD8+ T cell metabolic changes in tumor progression.
    Keywords:  Breast cancer; CD8(+) T cells; Immunometabolism; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166565
  5. Cancer Discov. 2022 Oct 14. OF1
    d-2HG Inhibits Effector T Cells by Altering Metabolic Programming.
      Uptake of the oncometabolite d-2HG impairs the metabolism and effector functions of CD8+ T cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-182
  6. Nat Rev Clin Oncol. 2022 Oct 10.
    Clinical implications of T cell exhaustion for cancer immunotherapy.
    Andrew Chow, Karlo Perica, Christopher A Klebanoff, Jedd D Wolchok.
      Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41571-022-00689-z
  7. Front Oncol. 2022 ;12 993437
    Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.
    Yixue Xia, Binghong Gao, Xue Zhang.
      Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells' metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.
    Keywords:  T cells exhaustion; hepatocellular carcinoma (HCC); immune cell; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2022.993437
  8. Nat Commun. 2022 Oct 13. 13(1): 6043
    TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine.
    Guo Li, Saranya Srinivasan, Liwen Wang, Chaoyu Ma, Kai Guo, Wenhao Xiao, Wei Liao, Shruti Mishra, Xin Zhang, Yuanzheng Qiu, Qianjin Lu, Yong Liu, Nu Zhang.
      TGF-β signaling is necessary for CD8+ T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+ TRM cells in the tumor microenvironment is associated with better prognosis, TGF-β-blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8+ T cells differentiate into TRMs in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8+ T cells are maintained in a stem-like state, but a proportion of cells lost TRM status and differentiate into CX3CR1+ effector CD8+ T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8+ T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent TRM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.
    DOI:  https://doi.org/10.1038/s41467-022-33768-x
  9. Front Immunol. 2022 ;13 977394
    T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy.
    Zhanyan Gao, Yang Feng, Jinhua Xu, Jun Liang.
      Immune-mediated inflammatory diseases(IMIDs) are referred to as highly disabling chronic diseases affecting different organs and systems. Inappropriate or excessive immune responses with chronic inflammation are typical manifestations. Usually in patients with chronic infection and cancer, due to long-term exposure to persistent antigens and inflammation microenvironment, T-cells are continuously stimulated and gradually differentiate into an exhausted state. Exhausted T-cells gradually lose effector function and characteristics of memory T-cells. However, existing studies have found that exhausted T-cells are not only present in the infection and tumor environment, but also in autoimmunity, and are associated with better prognosis of IMIDs. This suggests new prospects for the application of this reversible process of T-cell exhaustion in the treatment of IMID. This review will focus on the research progress of T-cell exhaustion in several IMIDs and its potential application for diagnosis and treatment in IMIDs.
    Keywords:  T-cell exhaustion; autoimmunity; immune-mediated inflammatory diseases(IMIDs); immunotherapy; inhibitory receptor; therapeutic exhaustion
    DOI:  https://doi.org/10.3389/fimmu.2022.977394
  10. EMBO Rep. 2022 Oct 10. e54685
    Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
    Aleksandra Lopez Krol, Hannah P Nehring, Felix F Krause, Anne Wempe, Hartmann Raifer, Andrea Nist, Thorsten Stiewe, Wilhelm Bertrams, Bernd Schmeck, Maik Luu, Hanna Leister, Ho-Ryun Chung, Uta-Maria Bauer, Till Adhikary, Alexander Visekruna.
      Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.
    Keywords:  Th17 cells; Tregs; histone lactylation; immunometabolism; lactate
    DOI:  https://doi.org/10.15252/embr.202254685
  11. Front Immunol. 2022 ;13 986847
    Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
    Xiaojin Feng, Xue Li, Na Liu, Ningning Hou, Xiaodong Sun, Yongping Liu.
      The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.
    Keywords:  CD4+ T cells; autoimmune diseases; glutamine; glutaminolysis; immune response
    DOI:  https://doi.org/10.3389/fimmu.2022.986847
  12. Cytokine. 2022 Oct 05. pii: S1043-4666(22)00266-6. [Epub ahead of print]161 156057
    Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes.
    Vance Holt, Björn Morén, Claes Fryklund, Robert A Colbert, Karin G Stenkula.
      During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance. Here, we show that the pro-inflammatory cytokines IFNγ and TNF together rapidly induce glucose uptake, glycolysis, and glycolytic capacity in cultured keratinocytes. Furthermore, we found that acute IFNγ and TNF stimulation induces glucose transporter 4 (GLUT4) translocation to the plasma membrane and engages AMPK-dependent intracellular signaling. Together, these findings suggest acute cytokine-induced glucose metabolism in keratinocytes could contribute to inflammation in psoriatic disease, and that GLUT4 is involved in these processes.
    Keywords:  GLUT4; Glucose uptake; IFNγ; Keratinocytes; TNF
    DOI:  https://doi.org/10.1016/j.cyto.2022.156057
  13. Nat Cell Biol. 2022 Oct 13.
    Metabolic communication in the tumour-immune microenvironment.
    Kung-Chi Kao, Stefania Vilbois, Chin-Hsien Tsai, Ping-Chih Ho.
      The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour-immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.
    DOI:  https://doi.org/10.1038/s41556-022-01002-x
  14. FEBS J. 2022 Oct 11.
    Senescent cells in the brain and where to find them.
    Noa Rachmian, Valery Krizhanovsky.
      Cellular senescence is a process in which cells change their characteristic phenotype in response to stress and enter a state of prolonged cell cycle arrest accompanied by a distinct secretory phenotype. Cellular senescence has both beneficial and detrimental outcomes. With age, senescent cells progressively accumulate in tissues and might be the bridge connecting ageing to many age-related pathologies. In recent years, evidence emerged supporting the accumulation of brain senescent cells during neurological disorders and ageing. Here, we will discuss the different brain cell populations that exhibit a senescent phenotype. Subsequently, we will explore several senolytic strategies which have been developed to eliminate senescent cells. Finally, we will examine their potential to directly eliminate these senescent brain cells.
    Keywords:  Ageing; Blood-brain barrier; Cellular Senescence; Neurodegeneration; Senolytics
    DOI:  https://doi.org/10.1111/febs.16649
  15. Nat Rev Immunol. 2022 Oct 10.
    Boosting cytotoxic T cells for immunotherapy.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-022-00793-2
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