bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–06–30
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Reversal of T-cell exhaustion: Mechanisms and synergistic approaches.
  2. Deletion of CD38 enhances CD19 chimeric antigen receptor T cell function.
  3. Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.
  4. Identification of different functions of CD8+ T cell subpopulations by a novel monoclonal antibody.
  5. Ferroptotic stress drives liver aging and metabolic dysfunction.
  6. One-carbon metabolism shapes T cell immunity in cancer.
  7. Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.
  8. Targeting a disintegrin and metalloprotease (ADAM) 17-CD122 axis enhances CD8+ T cell effector differentiation and anti-tumor immunity.
  9. Immunometabolism in atherosclerosis: a new understanding of an old disease.
  10. T-cell exhaustion in multiple myeloma.
  11. Lymphoid TCF1+CD39+CD8+ T cells maintain stem-like features and contribute to viral control.
  12. Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.
  13. Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy.
  1. Int Immunopharmacol. 2024 Jun 27. pii: S1567-5769(24)01092-0. [Epub ahead of print]138 112571
    Reversal of T-cell exhaustion: Mechanisms and synergistic approaches.
    Yang Hu, Yaqi Zhang, Fenfen Shi, Ruihan Yang, Jiayu Yan, Tao Han, Liping Guan.
      T cells suffer from long-term antigen stimulation and insufficient energy supply, leading to a decline in their effector functions, memory capabilities, and proliferative capacity, ultimately resulting in T cell exhaustion and an inability to perform normal immune functions in the tumor microenvironment. Therefore, exploring how to restore these exhausted T cells to a state with effector functions is of great significance. Exhausted T cells exhibit a spectrum of molecular alterations, such as heightened expression of inhibitory receptors, shifts in transcription factor profiles, and modifications across epigenetic, metabolic, and transcriptional landscapes. This review provides a comprehensive overview of various strategies to reverse T cell exhaustion, including immune checkpoint blockade, and explores the potential synergistic effects of combining multiple approaches to reverse T cell exhaustion. It offers new insights and methods for achieving more durable and effective reversal of T cell exhaustion.
    Keywords:  Combination therapy; Epigenetics; ICB; T-cell exhaustion; Tumor immune
    DOI:  https://doi.org/10.1016/j.intimp.2024.112571
  2. Mol Ther Oncol. 2024 Jun 20. 32(2): 200819
    Deletion of CD38 enhances CD19 chimeric antigen receptor T cell function.
    Kimberly Veliz, Feng Shen, Olga Shestova, Maksim Shestov, Alexander Shestov, Sara Sleiman, Tyler Hansen, Roddy S O'Connor, Saar Gill.
      Cell surface molecules transiently upregulated on activated T cells can play a counter-regulatory role by inhibiting T cell function. Deletion or blockade of such immune checkpoint receptors has been investigated to improve the function of engineered immune effector cells. CD38 is upregulated on activated T cells, and although there have been studies showing that CD38 can play an inhibitory role in T cells, how it does so has not fully been elucidated. In comparison with molecules such as PD1, CTLA4, LAG3, and TIM3, we found that CD38 displays more sustained and intense expression following acute activation. After deleting CD38 from human chimeric antigen receptor (CAR) T cells, we showed relative resistance to exhaustion in vitro and improved anti-tumor function in vivo. CD38 is a multifunctional ectoenzyme with hydrolase and cyclase activities. Reintroduction of CD38 mutants into T cells lacking CD38 provided further evidence supporting the understanding that CD38 plays a crucial role in producing the immunosuppressive metabolite adenosine and utilizing nicotinamide adenine dinucleotide (NAD) in human T cells. Taken together, these results highlight a role for CD38 as an immunometabolic checkpoint in T cells and lead us to propose CD38 deletion as an additional avenue for boosting CAR T cell function.
    Keywords:  CD38 enzyme; T cell exhaustion; cyclic-ADP ribose; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.omton.2024.200819
  3. Mol Oncol. 2024 Jun 22.
    Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.
    Josquin Moraly, Taisuke Kondo, Mehdi Benzaoui, Justyn DuSold, Sohan Talluri, Marie C Pouzolles, Christopher Chien, Valérie Dardalhon, Naomi Taylor.
      Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as "living drugs," their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post-translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic-based strategies to enhance T cell immunotherapy.
    Keywords:  T cells; anti‐tumor immunotherapy; chimeric antigen receptor; immunometabolism; nutrient transporters; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13691
  4. Immunology. 2024 Jun 24.
    Identification of different functions of CD8+ T cell subpopulations by a novel monoclonal antibody.
    Kantinan Chuensirikulchai, Supansa Pata, Witida Laopajon, Nuchjira Takheaw, Kamonporn Kotemul, Kanyaruck Jindaphun, Saichit Khummuang, Watchara Kasinrerk.
      The explicit identification of CD8+ T cell subpopulation is important for deciphering the role of CD8+ T cells for protecting our body against invading pathogens and cancer. Our generated monoclonal antibody (mAb), named FE-1H10, recognized two novel subpopulations of peripheral blood CD8+ T cells, FE-1H10+ and FE-1H10- CD8+ T cells. The molecule recognized by mAb FE-1H10 (FE-1H10 molecules) had a higher distribution on effector memory CD8+ T cell subsets. The functions of FE-1H10- and FE-1H10+ CD8+ T cells were investigated. T cell proliferation assays revealed that FE-1H10- CD8+ T cells exhibited a higher proliferation rate than FE-1H10+ CD8+ T cells, whereas FE-1H10+ CD8+ T cells produced higher levels of IFN-γ and TNF-α than FE-1H10- CD8+ T cells. In T cell cytotoxicity assays, FE-1H10+ CD8+ T cells were able to kill target cells better than FE-1H10- CD8+ T cells. RNA-sequencing analysis confirmed that these subpopulations were distinct: FE-1H10+ CD8+ T cells have higher expression of genes involved in effector functions (IFNG, TNF, GZMB, PRF1, GNLY, FASL, CX3CR1) while FE-1H10- CD8+ T cells have greater expression of genes related to memory CD8+ T cell populations (CCR7, SELL, TCF7, CD40LG). The results suggested that mAb FE-1H10 identifies two novel distinctive CD8+ T cell subpopulations. The FE-1H10+ CD8+ T cells carried a superior functionality in response to tumour cells. The uncover of these novel CD8+ T cell subpopulations may be the basis knowledge of an optional immunotherapy for the selection of potential CD8+ T cells in cancer treatment.
    Keywords:  CD8+ T cell subpopulation; CD8+ T cells; RNA sequencing; T lymphocytes; cell surface molecule; monoclonal antibody
    DOI:  https://doi.org/10.1111/imm.13826
  5. Nat Aging. 2024 Jun 26.
    Ferroptotic stress drives liver aging and metabolic dysfunction.
      
    DOI:  https://doi.org/10.1038/s43587-024-00654-8
  6. Trends Endocrinol Metab. 2024 Jun 25. pii: S1043-2760(24)00160-7. [Epub ahead of print]
    One-carbon metabolism shapes T cell immunity in cancer.
    Yajing Qiu, Ermei Xie, Haipeng Xu, Hongcheng Cheng, Guideng Li.
      One-carbon metabolism (1CM), comprising folate metabolism and methionine metabolism, serves as an important mechanism for cellular energy provision and the production of vital signaling molecules, including single-carbon moieties. Its regulation is instrumental in sustaining the proliferation of cancer cells and facilitating metastasis; in addition, recent research has shed light on its impact on the efficacy of T cell-mediated immunotherapy. In this review, we consolidate current insights into how 1CM affects T cell activation, differentiation, and functionality. Furthermore, we delve into the strategies for modulating 1CM in both T cells and tumor cells to enhance the efficacy of adoptively transferred T cells, overcome metabolic challenges in the tumor microenvironment (TME), and maximize the benefits of T cell-mediated immunotherapy.
    Keywords:  One-carbon metabolism; T cell fate; T cell-mediated immunotherapy; folate cycle; methionine cycle
    DOI:  https://doi.org/10.1016/j.tem.2024.05.010
  7. bioRxiv. 2024 Jun 12. pii: 2024.06.10.598377. [Epub ahead of print]
    Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.
    Nicholas J Maurice, Jami R Erickson, Caitlin S DeJong, Florian Mair, Alexis K Taber, Marie Frutoso, Laura V Islas, Anna-Lena Bg Vigil, Richard L Lawler, M Juliana McElrath, Evan W Newell, Lucas B Sullivan, Raj Shree, Stephen A McCartney.
      Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.
    DOI:  https://doi.org/10.1101/2024.06.10.598377
  8. Signal Transduct Target Ther. 2024 Jun 26. 9(1): 152
    Targeting a disintegrin and metalloprotease (ADAM) 17-CD122 axis enhances CD8+ T cell effector differentiation and anti-tumor immunity.
    Lina Sun, Anjun Jiao, Haiyan Liu, Renyi Ding, Ning Yuan, Biao Yang, Cangang Zhang, Xiaoxuan Jia, Gang Wang, Yanhong Su, Dan Zhang, Lin Shi, Chenming Sun, Aijun Zhang, Lianjun Zhang, Baojun Zhang.
      CD8+ T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8+ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8+ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8+ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8+ T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8+ T cells. Intriguingly, inhibition of ADAM17 in CD8+ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8+ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41392-024-01873-6
  9. Trends Biochem Sci. 2024 Jun 26. pii: S0968-0004(24)00146-4. [Epub ahead of print]
    Immunometabolism in atherosclerosis: a new understanding of an old disease.
    Michelangelo Certo, Mahsa Rahimzadeh, Claudio Mauro.
      Atherosclerosis, a chronic inflammatory condition, remains a leading cause of death globally, necessitating innovative approaches to target pro-atherogenic pathways. Recent advancements in the field of immunometabolism have highlighted the crucial interplay between metabolic pathways and immune cell function in atherogenic milieus. Macrophages and T cells undergo dynamic metabolic reprogramming to meet the demands of activation and differentiation, influencing plaque progression. Furthermore, metabolic intermediates intricately regulate immune cell responses and atherosclerosis development. Understanding the metabolic control of immune responses in atherosclerosis, known as athero-immunometabolism, offers new avenues for preventive and therapeutic interventions. This review elucidates the emerging intricate interplay between metabolism and immunity in atherosclerosis, underscoring the significance of metabolic enzymes and metabolites as key regulators of disease pathogenesis and therapeutic targets.
    Keywords:  chronic inflammatory disease; immune response; metabolic pathways; metabolic reprogramming; metabolites; therapeutic targets
    DOI:  https://doi.org/10.1016/j.tibs.2024.06.003
  10. Expert Rev Hematol. 2024 Jul;17(7): 295-312
    T-cell exhaustion in multiple myeloma.
    Krzysztof Żyłka, Tadeusz Kubicki, Lidia Gil, Dominik Dytfeld.
       INTRODUCTION: Chimeric Antigen Receptor (CAR) T-cells and Bispecific Antibodies (BsAb) are the leading platforms for redirecting the immune system against cells expressing the specific antigen, revolutionizing the treatment of hematological malignancies, including multiple myeloma (MM). In MM, drug-resistant relapses are the main therapy-limiting factor and the leading cause of why the disease is still considered incurable. T-cell-engaging therapies hold promise in improving the treatment of MM. However, the effectiveness of these treatments may be hindered by T-cell fitness. T-cell exhaustion is a condition of a gradual decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation.
    AREAS COVERED: This review examines findings about T-cell exhaustion in MM in the context of T-cell redirecting BsAbs and CAR-T treatment.
    EXPERT OPINION: The fitness of T-cells has become an important factor in the development of T-cell redirecting therapies. The way T-cell exhaustion relates to these therapies could affect the further development of CAR and BsAbs technologies, as well as the strategies used for clinical use. Therefore, this review aims to explore the current understanding of T-cell exhaustion in MM and its relationship to these therapies.
    Keywords:  BsAbs; CAR-T; Multiple myeloma; T-cell exhaustion; T-lymphocytes; bispecific antibodies; chimeric antigen receptor; hematologic neoplasms
    DOI:  https://doi.org/10.1080/17474086.2024.2370552
  11. Nat Immunol. 2024 Jun 25.
    Lymphoid TCF1+CD39+CD8+ T cells maintain stem-like features and contribute to viral control.
      
    DOI:  https://doi.org/10.1038/s41590-024-01889-8
  12. Immunohorizons. 2024 Jun 01. 8(6): 464-477
    Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.
    Gabriel J Rodriguez-Garcia, Diana K Graves, Muhammad B Mirza, Kamran Idrees, Young J Kim, Michael J Korrer, Jeffrey C Rathmell.
      PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other tumor microenvironmental factors may promote resistance to PD-1 blockade. We previously identified increased expression of the inhibitory receptor NKG2A on CD8+ T cells in HNSCC tumors compared with T cells in matching PBMC samples. Mechanisms that promote NKG2A expression and the role of NKG2A on human T cells in the tumor microenvironment, however, are uncertain. In this study, we show that tumor-conditioned media (TCM) of HNSCC cancer cell lines or ascites fluid from colorectal carcinoma patients is sufficient to induce the expression of NKG2A and other inhibitory receptors on activated CD8+ T cells isolated from PBMCs of healthy donors. Boiling or small molecular mass cutoff filtering did not eliminate the effect of TCM, suggesting that a small molecule promotes NKG2A. T cell activation in TCM decreased the basal and maximal mitochondrial respiration to metabolically restrain CD8+ T cells. Functionally, T cell activation in TCM reduced CD8+ T cell cytotoxicity as shown by lower production of cytokines, granzyme B, and perforin. Furthermore, TCM prevented CD8+ T cells from killing cancer cells in response to an anti-CD19/anti-CD3 bispecific T cell engager. Thus, a small secreted molecule from HNSCC cells can induce NKG2A expression and promote T cell dysfunction. Our findings may lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response and provide a model to study T cell dysfunction and impaired metabolism.
    DOI:  https://doi.org/10.4049/immunohorizons.2400046
  13. Cancer Immunol Res. 2024 Jun 24.
    Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy.
    Sarah Porte, Alexandra Audemard-Verger, Christian Wu, Aurélie Durand, Théo Level, Léa Giraud, Amélie Lombès, Mathieu Germain, Rémi Pierre, Bejamin Saintpierre, Mireille Lambert, Cédric Auffray, Carole Peyssonnaux, Francois Goldwasser, Sophie Vaulont, Marie-Clotilde Alves-Guerra, Renaud Dentin, Bruno Lucas, Bruno Martin.
      Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFN-γ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. This boost is associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the "adjuvant" effect of iron led to a marked slowdown of tumor-cell growth after tumor-cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes anti-tumor responses by increasing IFN-γ production by T cells. In addition, iron supplementation considerably improves the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in cancer patients, the quality and efficacy of the anti-tumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of anti-tumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0739
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