bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒08‒25
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
  2. PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
  3. Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
  4. Defining the niche for stem-like CD8+ T cell formation and function.
  5. Suppressive effect of the anesthetic propofol on the T cell function and T cell-dependent immune responses.
  6. Potential mechanisms of cancer stem-like progenitor T-cell bio-behaviours.
  7. Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
  8. NR4A ablation improves mitochondrial fitness for long persistence in human CAR-T cells against solid tumors.
  9. Oxidative Phosphorylation and Fatty Acid Oxidation in Slow-Aging Mice.
  10. Epithelial organoid supports resident memory CD8 T cell differentiation.
  11. Ex vivo T cell differentiation in adoptive immunotherapy manufacturing: Critical process parameters and analytical technologies.
  12. Manganese-mediated potentiation of antitumor immune responses by enhancing KLRG1+ Macrophage function.
  13. T cell trafficking in human chronic inflammatory diseases.
  1. Mol Cell. 2024 Aug 06. pii: S1097-2765(24)00619-1. [Epub ahead of print]
    Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
    Zhenxi Zhang, Yanting Yang, Yang Chen, Jingyu Su, Wenjing Du.
      The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
    Keywords:  CD8(+) T cell; DAPK1; antitumor immunity; fumarate; malic enzyme 2; metabolite sensing
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.021
  2. Sci Immunol. 2024 Aug 23. 9(98): eadn2717
    PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
    Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho.
      The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
    DOI:  https://doi.org/10.1126/sciimmunol.adn2717
  3. Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632
    Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
    Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.
      Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
    Keywords:  CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114632
  4. Curr Opin Immunol. 2024 Aug 17. pii: S0952-7915(24)00044-X. [Epub ahead of print]89 102454
    Defining the niche for stem-like CD8+ T cell formation and function.
    Benjamin J Broomfield, Joanna R Groom.
      TCF-1+ CD8+ T cell populations have emerged as critical determinants for long-lived immunological memory. This cell population has stem-like properties and is implicated in improved disease outcomes by driving sustained killing of infected cells and maintaining the immune-cancer equilibrium. During an immune response, several factors, including antigen deposition and affinity, the inflammatory milieu, and T cell priming dynamics, aggregate to skew CD8+ T cell differentiation. Although these mechanisms are altered between acute and chronic disease settings, phenotypically similar stem-like TCF-1+ CD8+ T cell states are formed in each of these settings. Here, we characterize the specialized microenvironments within lymph nodes and the tumor microenvironment, which foster the generation or re-activation of stem-like TCF-1+ CD8+ T cell populations. We highlight the potential for targeting the stem-like CD8+ T cell niche to enhance vaccination and cancer immunotherapy and to track the trajectory of stem-like CD8+ T cells as biomarkers of therapeutic efficacy.
    DOI:  https://doi.org/10.1016/j.coi.2024.102454
  5. Sci Rep. 2024 08 20. 14(1): 19337
    Suppressive effect of the anesthetic propofol on the T cell function and T cell-dependent immune responses.
    Waichi Yamamoto, Taisuke Hamada, Junpei Suzuki, Yuko Matsuoka, Miyuki Omori-Miyake, Makoto Kuwahara, Akira Matsumoto, Shunsuke Nomura, Amane Konishi, Toshihiro Yorozuya, Masakatsu Yamashita.
      General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.
    Keywords:  Antitumor immunity; Cytokine; Inflammation; Propofol; T cell
    DOI:  https://doi.org/10.1038/s41598-024-69987-z
  6. Clin Transl Med. 2024 Aug;14(8): e1817
    Potential mechanisms of cancer stem-like progenitor T-cell bio-behaviours.
    Ling Ni.
      In situations involving continuous exposure to antigens, such as chronic infections or cancer, antigen-specific CD8+ T cells can become dysfunctional or exhausted. This change is marked by increased expression levels of inhibitory receptors (PD-1 and Tim-3). Stem-like progenitor exhausted (Tpex) cells, a subset of exhausted cells that express TCF-1 and are mainly found in the lymph nodes, demonstrate the ability to self-renew and exhibit a high rate of proliferation. Tpex cells can further differentiate into transitional intermediate exhausted (Tex-int) cells and terminally exhausted (Tex-term) cells. Alternatively, they can directly differentiate into Tex-term cells. Tpex cells are the predominant subset that respond to immune checkpoint inhibitors (ICI), making them a prime candidate for improving the efficacy of ICI therapy. This review article aimed to present the latest developments in the field of Tpex formation, expansion, and differentiation in the context of cancer, as well as their responses to ICIs in cancer immunotherapy. Consequently, it may be possible to develop novel treatments that exclusively target Tpex cells, thus improving overall treatment outcomes. KEY POINTS: Tpex cells are located in lymph nodes and TLS. Several pathways control the differentiation trajectories of Tpex cells, including epigenetic factors, transcription factors, cytokines, age, sex, etc.
    Keywords:  CD8+ T cells; Tex‐int cells; Tex‐term cells; Tpex cells; cancer; immune checkpoint inhibitors
    DOI:  https://doi.org/10.1002/ctm2.1817
  7. Mol Ther. 2024 Aug 20. pii: S1525-0016(24)00541-0. [Epub ahead of print]
    Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
    Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong.
      Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.08.019
  8. J Immunother Cancer. 2024 Aug 16. pii: e008665. [Epub ahead of print]12(8):
    NR4A ablation improves mitochondrial fitness for long persistence in human CAR-T cells against solid tumors.
    Kensuke Nakagawara, Makoto Ando, Tanakorn Srirat, Setsuko Mise-Omata, Taeko Hayakawa, Minako Ito, Koichi Fukunaga, Akihiko Yoshimura.
      BACKGROUND: Antitumor effect of chimeric antigen receptor (CAR)-T cells against solid tumors is limited due to various factors, such as low infiltration rate, poor expansion capacity, and exhaustion of T cells within the tumor. NR4A transcription factors have been shown to play important roles in T-cell exhaustion in mice. However, the precise contribution of each NR4a factor to human T-cell differentiation remains to be clarified.METHODS: In this study, we deleted NR4A family factors, NR4A1, NR4A2, and NR4A3, in human CAR-T cells recognizing human epidermal growth factor receptor type 2 (HER2) by using the CRISPR/Cas9 system. We induced T-cell exhaustion in these cells in vitro through repeated co-culturing of CAR-T cells with Her2+A549 lung adenocarcinoma cells and evaluated cell surface markers such as memory and exhaustion phenotypes, proliferative capacity, cytokine production and metabolic activity. We validated the antitumor toxicity of NR4A1/2/3 triple knockout (TKO) CAR-T cells in vivo by transferring CAR-T cells into A549 tumor-bearing immunodeficient mice.
    RESULTS: Human NR4A-TKO CAR-T cells were resistant against exhaustion induced by repeated antigen stimulation in vitro, and maintained higher tumor-killing activity both in vitro and in vivo compared with control CAR-T cells. A comparison of the effectiveness of NR4A single, double, and TKOs demonstrated that triple KO was the most effective in avoiding exhaustion. Furthermore, a strong enhancement of antitumor effects by NR4A TKO was also observed in T cells from various donors including aged persons. Mechanistically, NR4A TKO CAR-T cells showed enhanced mitochondrial oxidative phosphorylation, therefore could persist for longer periods within the tumors.
    CONCLUSIONS: NR4A factors regulate CAR-T cell persistence and stemness through mitochondrial gene expression, therefore NR4A is a highly promising target for the generation of superior CAR-T cells against solid tumors.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Lung Cancer; Solid tumor; Stem cell
    DOI:  https://doi.org/10.1136/jitc-2023-008665
  9. Free Radic Biol Med. 2024 Aug 15. pii: S0891-5849(24)00605-1. [Epub ahead of print]
    Oxidative Phosphorylation and Fatty Acid Oxidation in Slow-Aging Mice.
    Ahmed M Elmansi, Richard A Miller.
      Oxidative metabolism declines with aging in humans leading to multiple metabolic ailments and subsequent inflammation. In mice, there is evidence of age-related suppression of fatty acid oxidation and oxidative phosphorylation in the liver, heart, and muscles. Many interventions that extend healthy lifespan of mice have been developed, including genetic, pharmacological, and dietary interventions. In this article, we review the literature on oxidative metabolism changes in response to those interventions. We also discuss the molecular pathways that mediate those changes, and their potential as targets for future longevity interventions.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.018
  10. Cell Rep. 2024 Aug 15. pii: S2211-1247(24)00971-9. [Epub ahead of print]43(8): 114621
    Epithelial organoid supports resident memory CD8 T cell differentiation.
    Max R Ulibarri, Ying Lin, Julian C Ramprashad, Geongoo Han, Mohammad H Hasan, Farha J Mithila, Chaoyu Ma, Smita Gopinath, Nu Zhang, J Justin Milner, Lalit K Beura.
      Resident memory T cells (TRMs) play a vital role in regional immune defense. Although laboratory rodents have been extensively used to study fundamental TRM biology, poor isolation efficiency and low cell survival rates have limited the implementation of TRM-focused high-throughput assays. Here, we engineer a murine vaginal epithelial organoid (VEO)-CD8 T cell co-culture system that supports CD8 TRM differentiation. These in-vitro-generated TRMs are phenotypically and transcriptionally similar to in vivo TRMs. Pharmacological and genetic approaches showed that transforming growth factor β (TGF-β) signaling plays a crucial role in their differentiation. The VEOs in our model are susceptible to viral infections and the CD8 T cells are amenable to genetic manipulation, both of which will allow a detailed interrogation of antiviral CD8 T cell biology. Altogether we have established a robust in vitro TRM differentiation system that is scalable and can be subjected to high-throughput assays that will rapidly add to our understanding of TRMs.
    Keywords:  CD8 resident memory T cells; CP: Developmental biology; CP: Immunology; T cell-epithelial cell crosstalk; antiviral CD8 T cell; in vitro differentiation; memory T cell differentiation; mucosal immune response; organoid modeling; vaginal epithelial organoids
    DOI:  https://doi.org/10.1016/j.celrep.2024.114621
  11. Biotechnol Adv. 2024 Aug 19. pii: S0734-9750(24)00128-9. [Epub ahead of print] 108434
    Ex vivo T cell differentiation in adoptive immunotherapy manufacturing: Critical process parameters and analytical technologies.
    Sixun Chen, Tan Dai Nguyen, Kang-Zheng Lee, Dan Liu.
      Adoptive immunotherapy shows great promise as a treatment for cancer and other diseases. Recent evidence suggests that the therapeutic efficacy of these cell-based therapies can be enhanced by the enrichment of less-differentiated T cell subpopulations in the therapeutic product, giving rise to a need for advanced manufacturing technologies capable of enriching of these subpopulations through regulation of T cell differentiation. Studies have shown that modifying certain critical process control parameters, such as cytokines, metabolites, amino acids, and culture environment, can effectively manipulate T cell differentiation in ex vivo cultures. Advanced process analytical technologies (PATs) are crucial for monitoring these parameters and the assessment of T cell differentiation during culture. In this review, we examine such critical process parameters and PATs, with an emphasis on their impact on enriching less-differentiated T cell population. We also discuss the limitations of current technologies and advocate for further efforts from the community to establish more stringent critical process parameters (CPPs) and develop more at-line/online PATs that are specific to T cell differentiation. These advancements will be essential to enable the manufacturing of more efficacious adoptive immunotherapy products.
    Keywords:  Adoptive immunotherapy manufacturing; Analytical technologies; Process analytical technologies (PATs); Process control strategies; T cell differentiation
    DOI:  https://doi.org/10.1016/j.biotechadv.2024.108434
  12. Int Immunopharmacol. 2024 Aug 16. pii: S1567-5769(24)01472-3. [Epub ahead of print]141 112951
    Manganese-mediated potentiation of antitumor immune responses by enhancing KLRG1+ Macrophage function.
    Liyan Ge, Hui Guo, Wei Zhou, Weifeng Shi, Jiawei Yue, Yumin Wu.
      Manganese (Mn) play a crucial role in various biological processes in the body. Studies have primarily focused on their ability to enhance immune cell function and activation against tumors, particularly in dendritic cells (DCs), macrophages, and T cells. Tumor-associated macrophages (TAMs) are often the most abundant immune cell population present in the tumor microenvironment (TME). Thus, it would be valuable to investigate the mechanism by which Mn2+ regulates TAMs' involvement in anti-tumor immunity, as it be crucial for advancing our understanding of cancer biology and developing new treatments for cancer. Here, in the present study we discovered that Mn2+ treatment led to a significant increase in KLRG1+ macrophages (KLRG1+ Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. Knocking down KLRG1 in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. Moreover, the changes in the polarization phenotype of KLRG1+ macrophages further lead to T cell proliferation and the polarization of CD4+ T cells towards a Th1 phenotype, thereby establishing a foundation for the antitumor immune response. Our study expands the understanding of the anti-tumor mechanism of Mn2+ and demonstrates, for the first time, that Mn2+ can regulate the function of KLRG1+ Mφ to participate in anti-tumor activities. These findings suggest that KLRG1 may represent a promising target for developing new tumor therapy.
    Keywords:  Antitumor; Immune responses; KLRG1; Macrophage; Manganese
    DOI:  https://doi.org/10.1016/j.intimp.2024.112951
  13. iScience. 2024 Aug 16. 27(8): 110528
    T cell trafficking in human chronic inflammatory diseases.
    Anna Giovenzana, Valentina Codazzi, Michele Pandolfo, Alessandra Petrelli.
      Circulating T cells, which migrate from the periphery to sites of tissue inflammation, play a crucial role in the development of various chronic inflammatory conditions. Recent research has highlighted subsets of tissue-resident T cells that acquire migratory capabilities and re-enter circulation, referred to here as "recirculating T cells." In this review, we examine recent advancements in understanding the biology of T cell trafficking in diseases where T cell infiltration is pivotal, such as multiple sclerosis and inflammatory bowel diseases, as well as in metabolic disorders where the role of T cell migration is less understood. Additionally, we discuss current insights into therapeutic strategies aimed at modulating T cell circulation across tissues and the application of state-of-the-art technologies for studying recirculation in humans. This review underscores the significance of investigating T trafficking as a novel potential target for therapeutic interventions across a spectrum of human chronic inflammatory diseases.
    Keywords:  components of the immune system; human metabolism; immunology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.110528
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