bims-imseme 2022-05-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–05–08
six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity.
Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.
Reversal of the T cell immune system reveals the molecular basis for T cell lineage fate determination in the thymus.
Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice.
Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.
Glycolytic and lipid oxidative metabolic programs are essential for freshly-isolated regulatory T cells in mice with sepsis.

Cancer Lett. 2022 Apr 28. pii: S0304-3835(22)00194-X. [Epub ahead of print]538 215710

Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity.

Luyan Shen, Yefei Xiao, Chaoting Zhang, Shance Li, Xia Teng, Likun Cui, Ting Liu, Nan Wu, Zheming Lu.

  The inadequate in vivo persistence of chimeric antigen receptor (CAR)-modified T cells has been shown to lead to poor therapeutic efficacy and disease recurrence. In vivo persistence is associated with the differentiation subsets infused, with less differentiated TN or TCM conferring superior renewal capacity and antitumor immunity compared to TEM or TEFF. However, ex vivo expanded CAR-T cells exhibit phenotypic heterogeneity with majority of TEM or TEFF subsets and very low populations of TN and TCM. The transition of differentiation subsets is closely correlated with T cell metabolism fitness. Effector T cell differentiation from TN or TCM requires glutamine uptake and metabolism. Using a CD19-specific CAR, we demonstrated that glutamine inhibition by adding the glutamine antagonist 6-Diazo-5-oxo-l-norleucine (DON) into the culture endows CAR-T cells with enhanced mitochondrial OXPHOS utilizing fatty acids and reduced glycolytic activity, and retains more TN or TCM subsets. DON- pretreated CAR-T cells exhibited stronger cytotoxic lysis in vitro and more robust elimination of tumor burdens in vivo. This study suggests that glutamine inhibition ex vivo would be a potential approach for modulating metabolism and differentiation state to improve the efficacy of CAR-T cell therapy.

Keywords:  Fatty acid oxidation; Glutamine antagonist; Glycolysis; Memory T cell; Mitochondrial OXPHOS

DOI:  https://doi.org/10.1016/j.canlet.2022.215710
Trends Endocrinol Metab. 2022 May 01. pii: S1043-2760(22)00059-5. [Epub ahead of print]

Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.

Anne Lise Ferrara, Antonietta Liotti, Antonio Pezone, Veronica De Rosa.

  The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4+CD25+ T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence. Moreover, changes in cellular metabolism couple with activation of immune pathways and epigenetic remodeling to finely tune the balance between T cell activation and tolerance. This Review summarizes these aspects and critically evaluates novel possibilities for developing therapeutic strategies to modulate immune tolerance through metabolism via epigenetic drugs.

Keywords:  Foxp3; T regulatory cells; epigenetic regulation; immune tolerance; metabolic flexibility

DOI:  https://doi.org/10.1016/j.tem.2022.04.002
Nat Immunol. 2022 Apr 29.

Reversal of the T cell immune system reveals the molecular basis for T cell lineage fate determination in the thymus.

Miho Shinzawa, E Ashley Moseman, Selamawit Gossa, Yasuko Mano, Abhisek Bhattacharya, Terry Guinter, Amala Alag, Xiongfong Chen, Maggie Cam, Dorian B McGavern, Batu Erman, Alfred Singer.

T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8-regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.

DOI: https://doi.org/10.1038/s41590-022-01187-1
iScience. 2022 May 20. 25(5): 104241

Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice.

Josephine Brown, Georges Abboud, Longhuan Ma, Seung-Chul Choi, Nathalie Kanda, Leilani Zeumer-Spataro, Jean Lee, Weidan Peng, Joy Cagmat, Tamas Faludi, Mansour Mohamadzadeh, Timothy Garrett, Laura Mandik-Nayak, Alexander Chervonsky, Andras Perl, Laurence Morel.

  A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.

Keywords:  Biological sciences; Cell biology; Human metabolism; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.104241
Cell Metab. 2022 Apr 23. pii: S1550-4131(22)00130-9. [Epub ahead of print]

Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.

Sarah A Best, Patrick M Gubser, Shalini Sethumadhavan, Ariena Kersbergen, Yashira L Negrón Abril, Joshua Goldford, Katherine Sellers, Waruni Abeysekera, Alexandra L Garnham, Jackson A McDonald, Clare E Weeden, Dovile Anderson, David Pirman, Thomas P Roddy, Darren J Creek, Axel Kallies, Gillian Kingsbury, Kate D Sutherland.

  The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

Keywords:  KEAP1; KRAS; STK11/Lkb1; glutaminase; glutamine; immune microenvironment; immunotherapy; lung adenocarcinoma; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.04.003
RSC Adv. 2020 May 27. 10(35): 21000-21008

Glycolytic and lipid oxidative metabolic programs are essential for freshly-isolated regulatory T cells in mice with sepsis.

Xiaomei Zhu, WenQing Ji, Shubin Guo, Di Zhu, Yue Yang, Xin Liu.

Immunometabolism determines the fate and function of regulatory T cells. The metabolic phenotype of regulatory T cells (Treg) is affected by various factors. The relationship between Treg metabolism and function of mice with sepsis is not clear. We used liquid chromatography and tandem mass spectrometry (LC-MS/MS) to analyze the metabolic profiles of freshly-isolated spleen Treg cells in mice with sepsis. It was found that in severe infection, activated Treg cells depend on glycolysis and fatty acid oxidation, and inhibition of metabolic pathways has a significant impact on the number and quality of Treg cells. Understanding the metabolic characteristics of Treg cells in the real environment in the body helps to grasp the function of Treg cells and even the overall immune status. Targeting the metabolic pathway of Treg may provide a new method for the treatment of sepsis.

DOI: https://doi.org/10.1039/d0ra01947j