bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒09‒25
nine papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Keeping track of the T cells that matter.
  2. m1A tRNA modification facilitates rapid T cell proliferation.
  3. Targeting cellular senescence in metabolic disease.
  4. DNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities.
  5. Immunometabolic alterations in lupus: where do they come from and where do we go from there?
  6. Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.
  7. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.
  8. Improving the reproducibility of metabolic research.
  9. The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.
  1. Nat Cancer. 2022 Sep;3(9): 1015-1017
    Keeping track of the T cells that matter.
    Paulien Kaptein, Daniela S Thommen.
      
    DOI:  https://doi.org/10.1038/s43018-022-00432-8
  2. Nat Immunol. 2022 Sep 23.
    m1A tRNA modification facilitates rapid T cell proliferation.
      
    DOI:  https://doi.org/10.1038/s41590-022-01302-2
  3. Mol Metab. 2022 Sep 16. pii: S2212-8778(22)00170-3. [Epub ahead of print] 101601
    Targeting cellular senescence in metabolic disease.
    Allyson K Palmer, Tamar Tchkonia, James L Kirkland.
      Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states.
    Keywords:  Adipose; Aging; Cellular senescence; Obesity; Senolytics
    DOI:  https://doi.org/10.1016/j.molmet.2022.101601
  4. Biomolecules. 2022 Sep 12. pii: 1282. [Epub ahead of print]12(9):
    DNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities.
    Lu Bai, Xiaolei Hao, Julia Keith, Yongqiang Feng.
      As a bona fide epigenetic marker, DNA methylation has been linked to the differentiation and function of regulatory T (Treg) cells, a subset of CD4 T cells that play an essential role in maintaining immune homeostasis and suppressing autoimmunity and antitumor immune response. DNA methylation undergoes dynamic regulation involving maintenance of preexisting patterns, passive and active demethylation, and de novo methylation. Scattered evidence suggests that these processes control different stages of Treg cell lifespan ranging from lineage induction to cell fate maintenance, suppression of effector T cells and innate immune cells, and transdifferentiation. Despite significant progress, it remains to be fully explored how differential DNA methylation regulates Treg cell fate and immunological function. Here, we review recent progress and discuss the questions and challenges for further understanding the immunological roles and mechanisms of dynamic DNA methylation in controlling Treg cell differentiation and function. We also explore the opportunities that these processes offer to manipulate Treg cell suppressive function for therapeutic purposes by targeting DNA methylation.
    Keywords:  DNA methylation; DNMT1; DNMT3A; DNMT3B; Foxp3; TET1; TET2; TET3; epigenetics; regulatory T cells
    DOI:  https://doi.org/10.3390/biom12091282
  5. Curr Opin Immunol. 2022 Sep 16. pii: S0952-7915(22)00092-9. [Epub ahead of print]78 102245
    Immunometabolic alterations in lupus: where do they come from and where do we go from there?
    Longhuan Ma, Tracoyia Roach, Laurence Morel.
      Systemic lupus erythematosus (SLE) is an autoimmune disease in which the overactivation of the immune system has been associated with metabolic alterations. Targeting the altered immunometabolism has been proposed to treat SLE patients based on their results obtained and mouse models of the disease. Here, we review the recent literature to discuss the possible origins of the alterations in the metabolism of immune cells in lupus, the dominant role of mitochondrial defects, technological advances that may move the field forward, as well as how targeting lupus immunometabolism may have therapeutic potential.
    DOI:  https://doi.org/10.1016/j.coi.2022.102245
  6. Neoplasma. 2022 Sep 22. pii: 220414N410. [Epub ahead of print]
    Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.
    Jing Chen, Shu-Ting Huang, Jian-Guo Chen, Jian-Hui He, Wu-Mei Lin, Zhi-Hong Huang, Hai-Yan Ye, Shan-Yang He.
      Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.
    DOI:  https://doi.org/10.4149/neo_2022_220414N410
  7. Nat Immunol. 2022 Sep 23.
    In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.
    Juan Dubrot, Peter P Du, Sarah Kate Lane-Reticker, Emily A Kessler, Audrey J Muscato, Arnav Mehta, Samuel S Freeman, Peter M Allen, Kira E Olander, Kyle M Ockerman, Clara H Wolfe, Fabius Wiesmann, Nelson H Knudsen, Hsiao-Wei Tsao, Arvin Iracheta-Vellve, Emily M Schneider, Andrea N Rivera-Rosario, Ian C Kohnle, Hans W Pope, Austin Ayer, Gargi Mishra, Margaret D Zimmer, Sarah Y Kim, Animesh Mahapatra, Hakimeh Ebrahimi-Nik, Dennie T Frederick, Genevieve M Boland, W Nicholas Haining, David E Root, John G Doench, Nir Hacohen, Kathleen B Yates, Robert T Manguso.
      The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.
    DOI:  https://doi.org/10.1038/s41590-022-01315-x
  8. Nat Metab. 2022 Sep;4(9): 1085
    Improving the reproducibility of metabolic research.
      
    DOI:  https://doi.org/10.1038/s42255-022-00653-2
  9. J Cell Biol. 2022 Nov 07. pii: e202202011. [Epub ahead of print]221(11):
    The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.
    Fabrizia Bonacina, Annalisa Moregola, Monika Svecla, David Coe, Patrizia Uboldi, Sara Fraire, Simona Beretta, Giangiacomo Beretta, Fabio Pellegatta, Alberico Luigi Catapano, Federica M Marelli-Berg, Giuseppe Danilo Norata.
      Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge.
    DOI:  https://doi.org/10.1083/jcb.202202011
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