bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒04‒07
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.
  2. Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.
  3. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.
  4. RAM is upregulated during T cell activation and is required for RNA cap formation and gene expression.
  5. Functional CRISPR screens in T cells reveal new opportunities for cancer immunotherapies.
  6. Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer.
  7. Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.
  8. Editorial: Regulation of metabolic rewiring in T-cell malignancies.
  9. Editorial: Metabolic modulation of cellular function.
  10. CD8-targeted IL2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool.
  11. Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk.
  1. iScience. 2024 Apr 19. 27(4): 109496
    Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.
    Nathalie A Reilly, Friederike Sonnet, Koen F Dekkers, Joanneke C Kwekkeboom, Lucy Sinke, Stan Hilt, Hayat M Suleiman, Marten A Hoeksema, Hailiang Mei, Erik W van Zwet, Bart Everts, Andreea Ioan-Facsinay, J Wouter Jukema, Bastiaan T Heijmans.
      T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.
    Keywords:  Cell biology; Human metabolism; Immunology; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109496
  2. Transpl Int. 2024 ;37 12330
    Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.
    Johan Noble, Zuzana Macek Jilkova, Caroline Aspord, Paolo Malvezzi, Miguel Fribourg, Leonardo V Riella, Paolo Cravedi.
      Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism.
    Keywords:  glycolysis; immune cells; metabolism; rejection; solid organ transplantation
    DOI:  https://doi.org/10.3389/ti.2024.12330
  3. Cell. 2024 Mar 28. pii: S0092-8674(24)00303-9. [Epub ahead of print]
    Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.
    Tianyu Cao, Wenyao Zhang, Qi Wang, Chen Wang, Wanqi Ma, Cangang Zhang, Minghui Ge, Miaomiao Tian, Jia Yu, Anjun Jiao, Liang Wang, Manjiao Liu, Pei Wang, Zhiyu Guo, Yun Zhou, Shuyi Chen, Wen Yin, Jing Yi, Hao Guo, Hua Han, Baojun Zhang, Kaichun Wu, Daiming Fan, Xin Wang, Yongzhan Nie, Yuanyuan Lu, Xiaodi Zhao.
      Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.
    Keywords:  ATF4; ER stress; T cell exhaustion; chemoresistance; gastric cancer; immune checkpoint; solute carrier; taurine; transcription regulation; tumor recurrence and metastasis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.011
  4. Discov Immunol. 2024 ;3(1): kyad021
    RAM is upregulated during T cell activation and is required for RNA cap formation and gene expression.
    Katarzyna Knop, Carolina Gomez-Moreira, Alison Galloway, Dimitrinka Ditsova, Victoria H Cowling.
      On T cell activation, upregulation of gene expression produces the protein required for the differentiation and proliferation of effector cell populations. RAM (RNMT-Activating Mini protein/RAMAC/Fam103a1), the cofactor of the RNA cap methyltransferase RNMT (RNA guanosine N-7 cap methyltransferase), is upregulated following activation. Formation of the RNA cap protects RNA during synthesis and guides RNA processing and translation. Using conditional gene deletion, we found that Ram expression stabilizes RNMT protein in T cells and is required for its upregulation on activation. When the Ram gene is deleted in naïve T cells, there are major impacts on activation-induced RNA cap formation and gene expression. Activated T cell proliferation is dependent on increased ribosome production; in Ram knockout T cells, activation-induced expression of ribosomal protein genes and snoRNAs is most severely reduced. Consistent with these changes, Ram deletion resulted in reduced protein synthesis, and reduced growth and proliferation of CD4 T cells. Deletion of Ram results in a similar but milder phenotype to Rnmt deletion, supporting the role of RAM as a RNMT cofactor.
    Keywords:  RNA cap; T cells; activation; transcription; transcriptomics; translation
    DOI:  https://doi.org/10.1093/discim/kyad021
  5. Mol Cancer. 2024 Apr 05. 23(1): 73
    Functional CRISPR screens in T cells reveal new opportunities for cancer immunotherapies.
    Minghua Xiang, Huayi Li, Yuanyuan Zhan, Ding Ma, Qinglei Gao, Yong Fang.
      T cells are fundamental components in tumour immunity and cancer immunotherapies, which have made immense strides and revolutionized cancer treatment paradigm. However, recent studies delineate the predicament of T cell dysregulation in tumour microenvironment and the compromised efficacy of cancer immunotherapies. CRISPR screens enable unbiased interrogation of gene function in T cells and have revealed functional determinators, genetic regulatory networks, and intercellular interactions in T cell life cycle, thereby providing opportunities to revamp cancer immunotherapies. In this review, we briefly described the central roles of T cells in successful cancer immunotherapies, comprehensively summarised the studies of CRISPR screens in T cells, elaborated resultant master genes that control T cell activation, proliferation, fate determination, effector function, and exhaustion, and highlighted genes (BATF, PRDM1, and TOX) and signalling cascades (JAK-STAT and NF-κB pathways) that extensively engage in multiple branches of T cell responses. In conclusion, this review bridged the gap between discovering element genes to a specific process of T cell activities and apprehending these genes in the global T cell life cycle, deepened the understanding of T cell biology in tumour immunity, and outlined CRISPR screens resources that might facilitate the development and implementation of cancer immunotherapies in the clinic.
    Keywords:  Adoptive cell therapy; CRISPR screen; Cancer immunotherapy; Immune checkpoint inhibitor; T cell; T cell exhaustion; Tumour immunity
    DOI:  https://doi.org/10.1186/s12943-024-01987-z
  6. bioRxiv. 2024 Mar 20. pii: 2024.03.19.585657. [Epub ahead of print]
    Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer.
    Inga-Maria Launonen, Erdogan Pekcan Erkan, Iga Niemiec, Ada Junquera, María Hincapié-Otero, Daria Afenteva, Zhihan Liang, Matilda Salko, Angela Szabo, Fernando Perez-Villatoro, Matias M Falco, Yilin Li, Giulia Micoli, Ashwini Nagaraj, Ulla-Maija Haltia, Essi Kahelin, Jaana Oikkonen, Johanna Hynninen, Anni Virtanen, Ajit J Nirmal, Tuulia Vallius, Sampsa Hautaniemi, Peter Sorger, Anna Vähärautio, Anniina Färkkilä.
      To uncover the intricate, chemotherapy-induced spatiotemporal remodeling of the tumor microenvironment, we conducted integrative spatial and molecular characterization of 97 high-grade serous ovarian cancer (HGSC) samples collected before and after chemotherapy. Using single-cell and spatial analyses, we identify increasingly versatile immune cell states, which form spatiotemporally dynamic microcommunities at the tumor-stroma interface. We demonstrate that chemotherapy triggers spatial redistribution and exhaustion of CD8+ T cells due to prolonged antigen presentation by macrophages, both within interconnected myeloid networks termed "Myelonets" and at the tumor stroma interface. Single-cell and spatial transcriptomics identifies prominent TIGIT-NECTIN2 ligand-receptor interactions induced by chemotherapy. Using a functional patient-derived immuno-oncology platform, we show that CD8+T-cell activity can be boosted by combining immune checkpoint blockade with chemotherapy. Our discovery of chemotherapy-induced myeloid-driven spatial T-cell exhaustion paves the way for novel immunotherapeutic strategies to unleash CD8+ T-cell-mediated anti-tumor immunity in HGSC.
    DOI:  https://doi.org/10.1101/2024.03.19.585657
  7. Front Immunol. 2024 ;15 1376962
    Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.
    Zeyu Huang, Xuehui Liu, Qinghao Guo, Yihang Zhou, Linlin Shi, Qingjin Cai, Shupei Tang, Qin Ouyang, Ji Zheng.
      Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.
    Keywords:  CD8+ T cell; extracellular vesicles; immunity; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1376962
  8. Front Oncol. 2024 ;14 1384469
    Editorial: Regulation of metabolic rewiring in T-cell malignancies.
    Santosh Kumar, Naveen Kumar Vishvakarma, Ajay Kumar.
      
    Keywords:  T cell malignancies; cytokines; melatonin; metabolic rewiring; miRNAs; redox dynamics
    DOI:  https://doi.org/10.3389/fonc.2024.1384469
  9. Front Cell Dev Biol. 2024 ;12 1395922
    Editorial: Metabolic modulation of cellular function.
    Or Kakhlon, Ann Saada, Pablo V Escriba.
      
    Keywords:  cell fate; drug discovery; metabolic pathways; metabolism; metabolomics
    DOI:  https://doi.org/10.3389/fcell.2024.1395922
  10. Cancer Discov. 2024 Apr 02.
    CD8-targeted IL2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool.
    Paulien Kaptein, Nadine Slingerland, Christina Metoikidou, Felix Prinz, Simone Brokamp, Mercedes Machuca-Ostos, Guido de Roo, Ton N M Schumacher, Yik A Yeung, Kelly D Moynihan, Ivana M Djuretic, Daniela S Thommen.
      Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune checkpoint blockade can restore antitumor T cell function in some patients, however most do not respond to this therapy, often despite T cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8-IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8-IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8-IL2 was able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for cancer patients.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1263
  11. Nat Commun. 2024 Apr 02. 15(1): 2835
    Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk.
    Alexander Piening, Emily Ebert, Carter Gottlieb, Niloufar Khojandi, Lindsey M Kuehm, Stella G Hoft, Kelly D Pyles, Kyle S McCommis, Richard J DiPaolo, Stephen T Ferris, Elise Alspach, Ryan M Teague.
      Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction is commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals with obesity is unclear. Here we use a mouse model of diet-induced obesity to investigate tumor-infiltrating CD8 + T cell responses in lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment with semaglutide. While both strategies reduce body mass, only dietary intervention restores T cell function and improves responses to immunotherapy. In mice exposed to a chemical carcinogen, obesity-related immune dysfunction leads to higher incidence of sarcoma development. However, impaired immunoediting in the obese environment enhances tumor immunogenicity, making the malignancies highly sensitive to immunotherapy. These findings offer insight into the complex interplay between obesity, immunity and cancer, and provide explanation for the obesity paradox observed in clinical immunotherapy settings.
    DOI:  https://doi.org/10.1038/s41467-024-47359-5
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