bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒10‒10
seven papers selected by
Dylan Ryan
University of Cambridge

  1. Blood Adv. 2021 Oct 04. pii: bloodadvances.2021005047. [Epub ahead of print]
      Natural killer (NK) cells are a population of innate immune cells which can rapidily kill cancer cells and produce cytokines such as interferon gamma (IFN-gamma). A key feature of NK cells is their ability to respond without prior sensitation, however it is now well established that NK cells can possess memory-like features. After activation with cytokines, NK cells demonstrate enhanced effector functions upon restimulation days or weeks later. This demonstrates that NK cells may be "trained" to be more effective killers and harnessed as more potent cancer immunotherapy agents. We have previously demonstrated that cellular metabolism is essential for NK cell responses, with NK cells upregulating both glycolysis and oxidative phosphorylation upon cytokine stimulation. Limiting NK cell metabolism results in reduced cytotoxicity and cytokine production. We have also demonstrated that defective NK cell responses in obesity are linked to defective cellular metabolism. In the current study we investigated if cellular metabolism is required during the initial period of NK cell cytokine training, and if NK cells from people with obesity (PWO) can be effectively trained. We show that increased flux through glycolysis and OXPHOS during the initial cytokine activation period is essential for NK cell training, as is the metabolic signalling factor Srepb. We show that NK cells from PWO, which are metabolically defective, display impaired NK cell training, which may have implications for immunotherapy in this particularly vulnerable group.
  2. Immunometabolism. 2021 Sep 24. 3(4): e210030
      Immunotherapy has underscored a revolution in cancer treatment. Yet, many patients fail to respond due to T cell exhaustion. Here, an intervention that restores mitochondrial function reversed the exhausted T cell phenotype to promote cytotoxicity and durable anti-tumour responses in vivo.
    Keywords:  IL-10; T cell; exhaustion; immunotherapy; metabolism; mitochondria
  3. J Lipid Atheroscler. 2021 Sep;10(3): 251-267
      Chronic inflammation is a hallmark of atherosclerosis and macrophages play a central role in controlling inflammation at all stages of atherosclerosis. In atherosclerosis, macrophages and monocyte-derived macrophages are continuously exposed to cholesterol, oxidized lipids, cell debris, cytokines, and chemokines. Not only do these stimuli induce a specific macrophage phenotype, but they also interact extensively, leading to macrophage heterogeneity in atherosclerotic plaques. Herein, we review the diverse phenotypes of macrophages, the mechanisms underlying macrophage activation, and the contributions of macrophages to atherosclerosis in this context. We also summarize recent studies on foamy macrophages and monocyte-derived macrophages in plaque during disease progression. We provide a comprehensive overview of transcriptional, epigenetic, and metabolic reprogramming of macrophages and discuss the emerging concepts of targeting cytokines and macrophages to modulate atherosclerosis.
    Keywords:  Atherosclerosis; Cytokines; Innate immune memory; Macrophage activation
  4. Mol Cell Proteomics. 2021 Oct 04. pii: S1535-9476(21)00131-6. [Epub ahead of print] 100159
      Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multi-omics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and their association with disease severity. We used multi-omics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell line models along with immune phenotyping of metabolite transporters in patient blood to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multi-omics data to regulate the viral reproduction in vitro. COVID-19 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, GLUT1, in CD8+ T-cells, intermediate and non-classical monocytes, and amino acid transporter, xCT, in classical, intermediate, and non-classical monocytes. In in vitro lung epithelial cell (Calu-3) infection model we found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that SARS-CoV-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.
  5. Trends Immunol. 2021 Oct 02. pii: S1471-4906(21)00178-2. [Epub ahead of print]
      The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies.
    Keywords:  CAR-T cells; PD-1; glycolysis; immunotherapy; lactate; metabolism; tumor immunology
  6. Front Genet. 2021 ;12 756471
      Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). HIV infection affects the functions and metabolism of T cells, which may determine the fate of patients; however, the specific pathways activated in different T-cell subtypes (CD4+ and CD8+ T cells) at different stages of infection remain unclear. We obtained transcriptome data of five individuals each with early HIV infection, chronic progressive HIV infection, and no HIV infection. Weighted gene co-expression network analysis was used to evaluate changes in gene expression to determine the antiviral response. An advanced metabolic algorithm was then applied to compare the alterations in metabolic pathways in the two T-cell subtypes at different infection stages. We identified 23 and 20 co-expressed gene modules in CD4+ T and CD8+ T cells, respectively. CD4+ T cells from individuals in the early HIV infection stage were enriched in genes involved in metabolic and infection-related pathways, whereas CD8+ T cells were enriched in genes involved in cell cycle and DNA replication. Three key modules were identified in the network common to the two cell types: NLRP1 modules, RIPK1 modules, and RIPK2 modules. The specific role of NLRP1 in the regulation of HIV infection in the human body remains to be determined. Metabolic functional analysis of the two cells showed that the significantly altered metabolic pathways after HIV infection were valine, leucine, and isoleucine degradation; beta-alanine metabolism; and PPAR signaling pathways. In summary, we found the core gene expression modules and different pathways activated in CD4+ and CD8+ T cells, along with changes in their metabolic pathways during HIV infection progression. These findings can provide an overall resource for establishing biomarkers to facilitate early diagnosis and potential guidance for new targeted therapeutic strategies.
    Keywords:  HIV infection; T cell; metabolomics; transcriptional modules; weighted gene co-expression network analysis
  7. Nat Biomed Eng. 2021 Sep;5(9): 983-997
      Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.