bims-imseme 2024-08-11 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–08–11
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Are immunosenescent T cells really senescent?
Characteristics and mechanisms of T-cell senescence: A potential target for cancer immunotherapy.
CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.
LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling.
The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
Ketone bodies rescue T cell impairments induced by low glucose availability.
Nrf2 as a regulator of energy metabolism and mitochondrial function.
Enhancing the Efficacy of CAR-T Cell Therapy: A Comprehensive Exploration of Cellular Strategies and Molecular Dynamics.
Hypoxia-Inducible Factor 1-Alpha (HIF-1α): An Essential Regulator in Cellular Metabolic Control.

Aging Cell. 2024 Aug 07. e14300

Are immunosenescent T cells really senescent?

Helena Slaets, Naomi Veeningen, Peter L J de Keizer, Niels Hellings, Sven Hendrix.

  Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases.

Keywords:  T‐cells; exhaustion‐T‐lymphocytes; immunosenescence‐aging; senescence

DOI:  https://doi.org/10.1111/acel.14300
Eur J Immunol. 2024 Aug 06. e2451093

Characteristics and mechanisms of T-cell senescence: A potential target for cancer immunotherapy.

Han Wu, Junru Li, Zhen Zhang, Yi Zhang.

  Immunosenescence, the aging of the immune system, leads to functional deficiencies, particularly in T cells, which undergo significant changes. While numerous studies have investigated age-related T-cell phenotypes in healthy aging, senescent T cells have also been observed in younger populations during pathological conditions like cancer. This review summarizes the recent advancements in age-associated alterations and markers of T cells, mechanisms, and the relationship between senescent T cells and the tumor microenvironment. We also discuss potential strategies for targeting senescent T cells to prevent age-related diseases and enhance tumor immunotherapy efficacy.

Keywords:  Aging; Immunotherapy; Tumor microenvironment; T‐cell senescence

DOI:  https://doi.org/10.1002/eji.202451093
Mol Ther Oncol. 2024 Sep 19. 32(3): 200847

CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.

Viviana Rubino, Prasad S Adusumilli, Undrakh Ganbaatar.

DOI: https://doi.org/10.1016/j.omton.2024.200847
Signal Transduct Target Ther. 2024 Aug 09. 9(1): 199

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling.

Roland C Schelker, Jessica Fioravanti, Fabio Mastrogiovanni, Jeremy G Baldwin, Nisha Rana, Peng Li, Ping Chen, Timea Vadász, Rosanne Spolski, Christoph Heuser-Loy, Dragana Slavkovic-Lukic, Pedro Noronha, Giuseppe Damiano, Laura Raccosta, Daniela Maggioni, Sree Pullugula, Jian-Xin Lin, Jangsuk Oh, Patrick Grandinetti, Mario Lecce, Leo Hesse, Emilia Kocks, Azucena Martín-Santos, Claudia Gebhard, William G Telford, Yun Ji, Nicholas P Restifo, Vincenzo Russo, Michael Rehli, Wolfgang Herr, Warren J Leonard, Luca Gattinoni.

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

DOI: https://doi.org/10.1038/s41392-024-01915-z
Immunity. 2024 Aug 02. pii: S1074-7613(24)00352-2. [Epub ahead of print]

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Christopher M Jackson, Ayush Pant, Wikum Dinalankara, John Choi, Aanchal Jain, Ryan Nitta, Eli Yazigi, Laura Saleh, Liang Zhao, Thomas R Nirschl, Christina M Kochel, Brandon Hwa-Lin Bergsneider, Denis Routkevitch, Kisha Patel, Kwang Bog Cho, Stephany Tzeng, Sarah Y Neshat, Young-Hoon Kim, Barbara J Smith, Maria Cecilia Ramello, Elena Sotillo, Xinnan Wang, Jordan J Green, Chetan Bettegowda, Gordon Li, Henry Brem, Crystal L Mackall, Drew M Pardoll, Charles G Drake, Luigi Marchionni, Michael Lim.

  Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Keywords:  CD8(+) T cell hypofunction; Meteorin-like protein; T cell exhaustion; anti-tumor immunity; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.immuni.2024.07.003
Eur J Nutr. 2024 Aug 06.

Ketone bodies rescue T cell impairments induced by low glucose availability.

Arianna Ferrari, Jessica Filoni, Carla Di Dedda, Lorenzo Piemonti, Paolo Monti.

   PURPOSE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).
METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.

Keywords:  Immunometabolism; Ketogenic diet; T cells; Type 1 diabetes

DOI:  https://doi.org/10.1007/s00394-024-03469-w
FEBS Lett. 2024 Aug 08.

Nrf2 as a regulator of energy metabolism and mitochondrial function.

Alina Luchkova, Ana Mata, Susana Cadenas.

  Nuclear factor erythroid-2-related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.

Keywords:  Nrf2; energy metabolism; metabolic reprogramming; mitochondria; oxidative stress; redox signaling

DOI:  https://doi.org/10.1002/1873-3468.14993
J Cancer Immunol (Wilmington). 2024 ;6(1): 20-28

Enhancing the Efficacy of CAR-T Cell Therapy: A Comprehensive Exploration of Cellular Strategies and Molecular Dynamics.

Mehmet A Baysal, Abhijit Chakraborty, Apostolia M Tsimberidou.

  The emergence of chimeric antigen receptor T cell (CAR-T cell) therapy has revolutionized cancer treatment, particularly for hematologic malignancies. This commentary discusses developments in CAR-T cell therapy, focusing on the molecular mechanisms governing T cell fate and differentiation. Transcriptional and epigenetic factors play a pivotal role in determining the specificity, effectiveness, and durability of CAR-T cell therapy. Understanding these mechanisms is crucial to improve the efficacy and decrease the adverse events associated with CAR-T cell therapies, unlocking the full potential of these approaches. T cell differentiation in CAR-T cell product manufacturing plays an important role in clinical outcomes. A positive correlation exists between the clinical efficacy of CAR-T cell therapy and signatures of memory, whereas a negative correlation has been observed with signatures of effector function or exhaustion. The effectiveness of CAR-T cell products is likely influenced by T-cell frequency and by their ability to proliferate, which is closely linked to early T cell differentiation. The differentiation process involving distinct T memory cell subsets is initiated upon antigen elimination, indicating infection resolution. In chronic infections or cancer, T cells may undergo exhaustion, marked by continuous inhibitory receptor expression, decreased cytokine production, and diminished proliferative capacity. Other cell subsets, such as CD4+ T cells, innate-like T lymphocytes, NKT cells, and cord blood-derived hematopoietic stem cells, offer unique advantages in developing the next-generation CAR-T cell-based therapies. Future research should focus on optimizing T-cell-enhancing approaches and developing strategies to potentially cure patients with hematological diseases and solid tumors.

Keywords:  CAR-T cell therapy; CD4+ T cells; Cancer immunotherapy; Cord blood-derived hematopoietic stem cells; Innate-like T lymphocytes; Interleukin-15 (IL-15); T cell subsets; Tumor targeting

DOI:  https://doi.org/10.33696/cancerimmunol.6.080
Cureus. 2024 Jul;16(7): e63852

Hypoxia-Inducible Factor 1-Alpha (HIF-1α): An Essential Regulator in Cellular Metabolic Control.

Mohd Basheeruddin, Sana Qausain.

  The element that causes hypoxia when the von Hippel-Lindau (VHL) protein is not functioning is hypoxia-inducible factor 1-alpha (HIF-1α), which is the essential protein linked to cell control under hypoxia. Consequently, in situations where cells are oxygen-deficient, HIF-1α carries out a variety of essential functions. Citations to relevant literature support the notion that HIF-1α regulates the mitochondrial and glycolytic pathways, as well as the transition from the former to the latter. Cells with limited oxygen supply benefit from this change, which is especially beneficial for the inhibition of the mitochondrial electron transport chain and enhanced uptake of glucose and lactate. During hypoxic stress, HIF-1α also controls proline and glycolytic transporters such as lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). These mechanisms help the cell return to homeostasis. Therefore, through metabolic change promoting adenosine triphosphate (ATP) synthesis and reducing reactive oxygen species (ROS) creation, HIF-1α may have a role in reducing oxidative stress in cells. This evidence, which describes the function of HIF-1α in many molecular pathways, further supports the notion that it is prognostic and that it contributes to hypoxic cell adaption. Understanding more about disorders, including inflammation, cancer, and ischemia, is possible because of HIF-1α's effect on metabolic changes. Gaining knowledge about the battle between metabolism, which is directed by HIF-1α, would help advance the research on pathophysiological situations involving dysregulated hypoxia and metabolism.

Keywords:  function of mitochondria; glut1; hif-1α; ldha; ros; targets for therapy

DOI:  https://doi.org/10.7759/cureus.63852