bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–01–05
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
  2. T cell metabolism in kidney immune homeostasis.
  3. The T cell receptor sequence influences the likelihood of T cell memory formation.
  4. STC1 encapsulated in small extracellular vesicles from laryngeal squamous cell carcinoma cells induces CD8+ T cell dysfunction by reprogramming tumor-associated macrophages into M2-like macrophages.
  5. Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response.
  6. High CD38 expression defines a mitochondrial function-adapted CD8+ T cell subset with implications for lung cancer immunotherapy.
  7. Immunometabolic shifts in autoimmune disease: Mechanisms and pathophysiological implications.
  8. Engineering immunity using metabolically active polymeric nanoparticles.
  9. The phospholipid kinase PIKFYVE is essential for Th17 differentiation.
  10. Interplay between CD28 and PD-1 in T cell immunotherapy.
  11. Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis.
  1. Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00321-7. [Epub ahead of print]
    Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
    Letizia Rumiano, Teresa Manzo.
      Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.
    Keywords:  CD8 T cells; antitumor immunity; immunotherapy; lipids; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.11.014
  2. Front Immunol. 2024 ;15 1498808
    T cell metabolism in kidney immune homeostasis.
    Zikang Liu, Binbin Dai, Jiwen Bao, Yangbin Pan.
      Kidney immune homeostasis is intricately linked to T cells. Inappropriate differentiation, activation, and effector functions of T cells lead to a spectrum of kidney disease. While executing immune functions, T cells undergo a series of metabolic rewiring to meet the rapid energy demand. The key enzymes and metabolites involved in T cell metabolism metabolically and epigenetically modulate T cells' differentiation, activation, and effector functions, thereby being capable of modulating kidney immune homeostasis. In this review, we first summarize the latest advancements in T cell immunometabolism. Second, we outline the alterations in the renal microenvironment under certain kidney disease conditions. Ultimately, we highlight the metabolic modulation of T cells within kidney immune homeostasis, which may shed light on new strategies for treating kidney disease.
    Keywords:  T cell; cellular metabolism; immune homeostasis; kidney disease; microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1498808
  3. Cell Rep. 2024 Dec 27. pii: S2211-1247(24)01449-9. [Epub ahead of print]44(1): 115098
    The T cell receptor sequence influences the likelihood of T cell memory formation.
    Kaitlyn A Lagattuta, Ayano C Kohlgruber, Nouran S Abdelfattah, Aparna Nathan, Laurie Rumker, Michael E Birnbaum, Stephen J Elledge, Soumya Raychaudhuri.
      The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.
    Keywords:  CP: Immunology; T-cells; TCR; activation; immunology; memory; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115098
  4. Cancer Immunol Immunother. 2025 Jan 03. 74(2): 64
    STC1 encapsulated in small extracellular vesicles from laryngeal squamous cell carcinoma cells induces CD8+ T cell dysfunction by reprogramming tumor-associated macrophages into M2-like macrophages.
    Xiaoxue Chen, Zhigang Zhao, Rui Zhao, Wenjing Li, Xinyu Liu, Linli Tian, Ming Liu.
       BACKGROUND: Tumor-derived small extracellular vesicles (sEVs) play an essential role in reprogramming the tumor microenvironment. Metabolic reprogramming is an essential prerequisite for M2 polarization of tumor-associated macrophages (TAMs). This M2 phenotype is closely related to the immune dysfunction of CD8+ T cells and subsequent tumor progression. This study evaluates the role of laryngeal squamous cell carcinoma cell-derived small extracellular vesicles (LSCC-sEVs) in M2 polarization of TAMs and CD8+ T cell dysfunction, and delineates the underlying mechanisms.
    METHODS: Human leukemia monocyte cell line (THP-1) was induced to differentiate into M0 macrophages using phorbol 12-myristate 13-acetate. M0 macrophages were incubated with sEVs derived from LSCC cells TU212. CD8+T cells, extracted from peripheral blood mononuclear cells of healthy volunteer donors, were co-cultured with the LSCC-sEV-treated M0 macrophages to evaluate their proliferation, and immune function. The role of LSCC-sEVs was investigated in macrophage tumor-bearing mouse models.
    RESULTS: LSCC-sEVs promoted TAM M2 polarization and impaired CD8+ T cell function, attributing to PD-L1 expression upregulation. In addition, suppression of metabolic reprogramming could partially reverse LSCC-sEV-induced CD8+ T cell dysfunction. STC-1 was found highly enriched in LSCC-sEVs. Knockdown of STC1 abrogated metabolic reprogramming of TAMs into M2-like macrophages and restored CD8+ T cell function. Importantly, in vivo results showed that LSCC-sEVs transform TAMs into M2 phenotype by mediating metabolic reprogramming and induce CD8+ T cell dysfunction, ultimately accelerating tumor growth.
    CONCLUSION: Our data reveal a previously undescribed role for LSCC-sEVs in the regulation of M2 polarization of TAMs and immune cell function through STC1 mediated metabolic reprogramming.
    Keywords:  CD8+ T cell dysfunction; Laryngeal squamous cell carcinoma; M2 polarization; Metabolic reprogramming; STC1; Small extracellular vesicles; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00262-024-03915-y
  5. Nat Immunol. 2025 Jan;26(1): 68-81
    Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response.
    Kole R DeGolier, Etienne Danis, Marc D'Antonio, Jennifer Cimons, Michael Yarnell, Ross M Kedl, M Eric Kohler, James P Scott-Browne, Terry J Fry.
      Although chimeric antigen receptor (CAR) T cells are effective against B-lineage malignancies, post-CAR relapse is common, and efficacy in other tumors is limited. These challenges may be addressed through rational manipulations to control CAR T cell function. Here we examine the impact of cognate T cell antigen experience on subsequent CD8+ CAR T cell activity. Prior antigen encounter resulted in superior effector function against leukemia expressing low target antigen density at the expense of reduced proliferative capacity and susceptibility to dysfunction at limiting CAR doses. Distinctive temporal transcriptomic and epigenetic profiles in naive-derived and memory-derived CAR T cells identified RUNX family transcription factors as potential targets to augment the function of naive-derived CD8+ CAR T cells. RUNX2 overexpression enhanced antitumor efficacy of mouse CAR T cells, dependent on prior cell state, and heightened human CAR T cell functions. Our data demonstrate that prior antigen experience of CAR T cells determines functional attributes and amenability to transcription factor-mediated functional enhancement.
    DOI:  https://doi.org/10.1038/s41590-024-02034-1
  6. Cancer Immunol Immunother. 2025 Jan 03. 74(2): 49
    High CD38 expression defines a mitochondrial function-adapted CD8+ T cell subset with implications for lung cancer immunotherapy.
    Lei-Lei Lv, Jia-Wei Zhai, Jia-Juan Wu, Gui-Qin Fan, Yao-Xin Zhang, Yu Shen, Qiu-Xia Qu, Cheng Chen.
      Despite identifying specific CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathways driving this process remain elusive. Given the potential role of CD38 in regulating CD8+ T cell function, we aimed to investigate the accumulation of CD38+CD8+ T cells in lung cancer and explore its role in immunotherapy resistance. Phenotypic analysis of tumoral CD8+ T cells from both lung cancer patients and immunotherapy-resistant preclinical models revealed that CD38-expressing CD8+ T cells consist of CD38hi and CD38int subsets. These cells exhibited higher expression of exhaustion markers and displayed dysregulated mitochondrial bioenergetics. Notably, increased levels of CD38hiCD8+ T cells in the peripheral, but not central, tumor microenvironment were associated with a favorable response to anti-PD-1 therapy in non-small-cell lung cancer and correlated with the depth of clinical regression. This was evidenced by the greater depletion of CD38hiCD8+ T cells in patients with higher regional CD38hiCD8+ T cell infiltration. In immune checkpoint blockade (ICB)-resistant murine lung cancer models, PD-L1 mAbs alone failed to effectively reduce CD38hiCD8+ T cell levels. Notably, combination therapy with PD-L1 mAbs and EGCG selectively restricted CD38hiCD8+ T cell infiltration and enhanced IFN-γ production, significantly improving survival in this carcinoma model. The restoration of immunotherapy sensitivity was linked to improved mitochondrial function in CD38hiCD8+ T cells, which was validated by the established relationship between IFN-γ production and mitochondrial metabolism. Collectively, our data highlight the role of CD38-coupled mitochondrial dysfunction in promoting CD8+ T cell exhaustion and intrinsic resistance to ICB therapy, thereby offering a rationale for targeting CD38 to enhance the therapeutic efficacy of PD-1 blockade in lung cancer.
    Keywords:  CD38; CD8+ T Cells; Immune checkpoint blockade; Lung cancer; Mitochondria; PD-1
    DOI:  https://doi.org/10.1007/s00262-024-03881-5
  7. Autoimmun Rev. 2024 Dec 30. pii: S1568-9972(24)00229-5. [Epub ahead of print] 103738
    Immunometabolic shifts in autoimmune disease: Mechanisms and pathophysiological implications.
    Yue Chen, Qingqing Lin, Hui Cheng, Qiyu Xiang, Wenxian Zhou, Jinyu Wu, Xiaobing Wang.
      Autoimmune diseases occur when the immune system abnormally attacks the body's normal tissues, causing inflammation and damage. Each disease has unique immune and metabolic dysfunctions during pathogenesis. In rheumatoid arthritis (RA), immune cells have different metabolic patterns and mitochondrial/lysosomal dysfunctions at different disease stages. In systemic lupus erythematosus (SLE), type I interferon (IFN) causes immune cell metabolic dysregulation, linking activation to metabolic shifts that may worsen the disease. In systemic sclerosis (SSc), mitochondrial changes affect fibroblast metabolism and the immune response. Idiopathic inflammatory myopathies (IIMs) patients have mitochondrial and metabolic issues. In primary Sjögren's syndrome (pSS), immune cell metabolism is imbalanced and mitochondrial damage can lead to cell/tissue damage. Metabolic reprogramming links cellular energy needs and immune dysfunctions, causing inflammation, damage, and symptoms in these diseases. It also affects immune cell functions like differentiation, proliferation, and secretion. This review discusses the potential of targeting metabolic pathways to restore immune balance, offering directions for future autoimmune disease research and treatment.
    Keywords:  Autoimmune diseases; Idiopathic inflammatory myopathies; Metabolic reprogramming; Primary Sjögren's syndrome; Rheumatoid arthritis; Systemic lupus erythematosus; Systemic sclerosis
    DOI:  https://doi.org/10.1016/j.autrev.2024.103738
  8. Trends Biotechnol. 2024 Dec 27. pii: S0167-7799(24)00345-7. [Epub ahead of print]
    Engineering immunity using metabolically active polymeric nanoparticles.
    Kate V Griffin, Michael N Saunders, Costas A Lyssiotis, Lonnie D Shea.
      Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.
    Keywords:  immunoengineering; immunometabolism; metabolic reprogramming; polymeric nanoparticle
    DOI:  https://doi.org/10.1016/j.tibtech.2024.11.016
  9. J Exp Med. 2025 Feb 03. pii: e20240625. [Epub ahead of print]222(2):
    The phospholipid kinase PIKFYVE is essential for Th17 differentiation.
    Douglas S Prado, Richard T Cattley, Andreza B Sonego, Parth Sutariya, Shuxian Wu, Mijoon Lee, William C Boggess, Mark J Shlomchik, William F Hawse.
      T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation. Herein, we discovered that PIKFYVE regulates kinase and transcription factor networks to promote Th17 differentiation. As a specific example, PtdIns(3,5)P2 directly stimulates mTORC1 kinase activity to promote cell division and differentiation pathways. Furthermore, PIKFYVE promotes STAT3 phosphorylation, which is required for Th17 differentiation. Chemical inhibition or CD4-specific deletion of PIKFYVE reduces Th17 differentiation and autoimmune pathology in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. Our findings identify molecular mechanisms by which PIKFYVE promotes Th17 differentiation and suggest that PIKFYVE is a potential therapeutic target in Th17-driven autoimmune diseases.
    DOI:  https://doi.org/10.1084/jem.20240625
  10. Vascul Pharmacol. 2024 Dec 27. pii: S1537-1891(24)00187-3. [Epub ahead of print] 107461
    Interplay between CD28 and PD-1 in T cell immunotherapy.
    Zuhayr Jafri, Jingwen Zhang, Connor H O'Meara, Anthony M Joshua, Christopher R Parish, Levon M Khachigian.
      Immune checkpoint therapy targeting the PD-1/PD-L1 axis has revolutionized the treatment of solid tumors. However, T cell exhaustion underpins resistance to current anti-PD-1 therapies, resulting in lower response rates in cancer patients. CD28 is a T cell costimulatory receptor that can influence the PD-1 signalling pathway (and vice versa). CD28 signalling has the potential to counter T cell exhaustion by serving as a potential complementary response to traditional anti-PD-1 therapies. Here we discuss the interplay between PD-1 and CD28 in T cell immunotherapy and additionally how CD28 transcriptionally modulates T cell exhaustion. We also consider clinical attempts at targeting CD28; the challenges faced by past attempts and recent promising developments.
    Keywords:  CD28; Immunotherapy; PD-1; T cell
    DOI:  https://doi.org/10.1016/j.vph.2024.107461
  11. Nat Commun. 2024 Dec 30. 15(1): 10860
    Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis.
    Runping Duan, Loujing Jiang, Tianfu Wang, Zhaohuai Li, Xiaoyang Yu, Yuehan Gao, Renbing Jia, Xianqun Fan, Wenru Su.
      Aging is associated with increased tumor metastasis and poor prognosis. However, how an aging immune system contributes to the process is unclear. Here, single-cell RNA sequencing reveals that in male mice, aging shifts the lung immune microenvironment towards a premetastatic niche, characterized by an increased proportion of IL-17-expressing γδT (γδ17) and neutrophils. Mechanistically, age-dependent downregulation of the immune trafficking receptor S1pr1 drives the expansion of γδ17. Compared to young mice, expanded γδ17 recruit tumor-promoting neutrophils with lower expression levels of CD62L and higher levels of C-kit and CXCR4. These neutrophils suppress the stemness and tumor-killing functions of CD8+ T cells in aged male mice. Accordingly, antibody-mediated depletion of γδT or neutrophils reduces tumor metastatic foci in aged animals, and the administration of the senolytic agent procyanidin C1 reverses the observed immune-mediated, tumor-promoting effects of aging. Thus, we uncover a γδ17-Neutrophil-CD8 axis that promotes aging-driven tumor metastasis in male mice and provides potential insights for managing metastatic tumors.
    DOI:  https://doi.org/10.1038/s41467-024-55164-3
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒05 at 6:39.