bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–12–08
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome.
  2. Targeting CD4+ T cell Exhaustion to Improve Future Immunotherapy Strategies.
  3. Nanotubes power up T cells.
  4. Flt3L enhances clonal diversification and selective expansion of intratumoral CD8+ T cells while differentiating into effector-like cells.
  5. Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies.
  6. Decoding T cell senescence in cancer: is revisiting required?
  7. Impact of immunological aging on T cell-mediated therapies in older adults with multiple myeloma and lymphoma.
  8. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.
  9. Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
  10. Modulation of TCR stimulation and pifithrin-α improves the genomic safety profile of CRISPR-engineered human T cells.
  11. Age-related changes in mammary gland increase tumorigenesis.
  12. Editorial: Chronic stress, telomeres and aging.
  13. Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.
  1. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2415119121
    Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome.
    David S Iu, Jessica Maya, Luyen T Vu, Elizabeth A Fogarty, Adrian J McNairn, Faraz Ahmed, Carl J Franconi, Paul R Munn, Jennifer K Grenier, Maureen R Hanson, Andrew Grimson.
      Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic analysis across T cell subsets by integrating single-cell RNA-seq, RNA-seq, and ATAC-seq and further analyzed CD8+ T cell subpopulations following symptom provocation. Specific subsets of CD8+ T cells, as well as certain innate T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated factors. Together, these data identify T cell exhaustion as a component of ME, a finding which may provide a basis for future therapies, such as checkpoint blockade, metabolic interventions, or drugs that target chronic viral infections.
    Keywords:  ATACseq; ME/CFS; T cell exhaustion; flow cytometry; single-cell RNAseq
    DOI:  https://doi.org/10.1073/pnas.2415119121
  2. Bull Math Biol. 2024 Dec 02. 87(1): 10
    Targeting CD4+ T cell Exhaustion to Improve Future Immunotherapy Strategies.
    Tyler Simmons, Doron Levy.
      As of late, reinvigoration of exhausted T cells as a form of immunotherapy against cancer has been a promising strategy. However, inconsistent results highlight the uncertainties in the current understanding of cellular exhaustion and the need for research and better treatment design. In our previous work, we utilized mathematical modeling and analysis to recapitulate and complement the biological understanding of exhaustion in response to growing tumors. The results of this work recognized that the population size of progenitor exhausted CD8+ T cells played a larger factor in tumor control compared to cytotoxic abilities. From this notion, it was theorized that exhaustion in CD4+ T cells, which are known to help coordinate and promote the size of the CD8+ T cell response, would be a significant component of tumor control. To test this theory, this paper expands on the previous mathematical framework by incorporating CD4+ T cells and the exhaustion they face in response to tumoral settings. Analysis of this model supports our theory, indicating that targeting CD4+ T cell exhaustion would have a potentially large impact on tumor burden and should be investigated along with current immunotherapy strategies of exhausted CD8+ T cell reinvigoration. Ultimately, this work narrows the scope of future research, providing a potential target for improved therapeutic efforts.
    Keywords:  Exhaustion; Immunosuppression; Immunotherapy; Plasticity; Proliferation; Stalemate
    DOI:  https://doi.org/10.1007/s11538-024-01389-8
  3. Nat Rev Cancer. 2024 Dec 03.
    Nanotubes power up T cells.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-024-00782-8
  4. Cell Rep. 2024 Nov 30. pii: S2211-1247(24)01374-3. [Epub ahead of print]43(12): 115023
    Flt3L enhances clonal diversification and selective expansion of intratumoral CD8+ T cells while differentiating into effector-like cells.
    Dongmin Chun, Jiyeon Park, Seulgi Lee, Hyo Jae Kim, Jong-Eun Park, Suk-Jo Kang.
      PD-1 blockade enhances anti-tumoral CD8+ T cell responses via type 1 conventional dendritic cells (cDC1s), but how cDC1s change the properties of intratumoral CD8+ T cells remains to be determined. Here, we identified two populations of intratumoral CD8+ T cells distinguished by their expression of asialo-ganglio-N-tetraosylceramide (asGM1). asGM1neg and asGM1posCD8+ T cells show enriched expression of genes characteristic for precursor exhausted T (Tpex) cells and terminally exhausted T (Tex) cells, respectively. The in situ expression of Flt3L or inhibition of PD-1 each promote the differentiation of asGM1negCD8+ T cells into asGM1posCD8+ T cells via interleukin-12 (IL-12) while also increasing the expression of Tpex and effector-like T cell-associated genes and their effector functions. Both interventions selectively expand CD8+ T cells, but only Flt3L expression broadens their T cell receptor (TCR) repertoire. These data indicate the distinct role of Flt3L in diversifying the TCR repertoire, offering potential solutions for immune checkpoint blockade-resistant cancers.
    Keywords:  CP: Cancer; CP: Immunology; Flt3L; PD-1; TCR repertoire; Tex; Tpex; asGM1; cDC1; immunotherapy
    DOI:  https://doi.org/10.1016/j.celrep.2024.115023
  5. Blood Cancer J. 2024 Dec 03. 14(1): 213
    Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies.
    Zhongfei Tao, Zuzana Chyra, Jana Kotulová, Piotr Celichowski, Jana Mihályová, Sandra Charvátová, Roman Hájek.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.
    DOI:  https://doi.org/10.1038/s41408-024-01193-6
  6. Semin Cancer Biol. 2024 Nov 28. pii: S1044-579X(24)00087-7. [Epub ahead of print]
    Decoding T cell senescence in cancer: is revisiting required?
    Sophia Magkouta, Efrosyni Markaki, Konstantinos Evangelou, Russell Petty, Panayotis Verginis, Vassilis Gorgoulis.
      Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term "senescence" has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of "truly" senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.
    Keywords:  T- cell; cancer; cellular senescence; immunosenescence; therapy
    DOI:  https://doi.org/10.1016/j.semcancer.2024.11.003
  7. J Immunother Cancer. 2024 Dec 02. pii: e009462. [Epub ahead of print]12(12):
    Impact of immunological aging on T cell-mediated therapies in older adults with multiple myeloma and lymphoma.
    Fabian Ullrich, Paul J Bröckelmann, Amin T Turki, Abdullah M Khan, Elena-Diana Chiru, Marcus Vetter, Bastian von Tresckow, Rainer Wirth, Raul Cordoba, Valentín Ortiz-Maldonado, Tamas Fülöp, Nina Rosa Neuendorff.
      The treatment landscape for lymphoma and multiple myeloma, which disproportionally affect older adults, has been transformed by the advent of T cell-mediated immunotherapies, including immune checkpoint inhibition, T cell-engaging bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy, during the last decade. These treatment modalities re-enable the patient's own immune system to combat malignant cells and offer the potential for sustained remissions and cure for various diseases.Age profoundly affects the physiological function of the immune system. The process of biological aging is largely driven by inflammatory signaling, which is reciprocally fueled by aging-related alterations of physiology and metabolism. In the T cell compartment, aging contributes to T cell senescence and exhaustion, increased abundance of terminally differentiated cells, a corresponding attrition in naïve T cell numbers, and a decrease in the breadth of the receptor repertoire. Furthermore, inflammatory signaling drives aging-related pathologies and contributes to frailty in older individuals. Thus, there is growing evidence of biological aging modulating the efficacy and toxicity of T cell-mediated immunotherapies.Here, we review the available evidence from biological and clinical studies focusing on the relationship between T cell-mediated treatment of hematologic malignancies and age. We discuss biological features potentially impacting clinical outcomes in various scenarios, and potential strategies to improve the safety and efficacy of immune checkpoint inhibitors, T cell-engaging bispecific antibodies, and CAR-T cell therapy in older patients.
    Keywords:  Bispecific T cell engager - BiTE; Chimeric antigen receptor - CAR; Hematologic Malignancies; Immunotherapy; T cell
    DOI:  https://doi.org/10.1136/jitc-2024-009462
  8. Chem Soc Rev. 2024 Dec 02.
    Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.
    Muye Ma, Yongliang Zhang, Kanyi Pu, Wei Tang.
      Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
    DOI:  https://doi.org/10.1039/d4cs00679h
  9. EMBO Rep. 2024 Dec 02.
    Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
    Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski.
      T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.
    Keywords:  Autoimmunity; Calcium; MCU; Mitochondria; T-cell
    DOI:  https://doi.org/10.1038/s44319-024-00313-4
  10. Cell Rep Med. 2024 Nov 26. pii: S2666-3791(24)00617-7. [Epub ahead of print] 101846
    Modulation of TCR stimulation and pifithrin-α improves the genomic safety profile of CRISPR-engineered human T cells.
    Laurenz T Ursch, Jule S Müschen, Julia Ritter, Julia Klermund, Bettina E Bernard, Saskia Kolb, Linda Warmuth, Geoffroy Andrieux, Gregor Miller, Marina Jiménez-Muñoz, Fabian J Theis, Melanie Boerries, Dirk H Busch, Toni Cathomen, Kathrin Schumann.
      CRISPR-engineered chimeric antigen receptor (CAR) T cells are at the forefront of novel cancer treatments. However, several reports describe the occurrence of CRISPR-induced chromosomal aberrations. So far, measures to increase the genomic safety of T cell products focused mainly on the components of the CRISPR-Cas9 system and less on T cell-intrinsic features, such as their massive expansion after T cell receptor (TCR) stimulation. Here, we describe driving forces of indel formation in primary human T cells. Increased T cell activation and proliferation speed correlate with larger deletions. Editing of non-activated T cells reduces the risk of large deletions with the downside of reduced knockout efficiencies. Alternatively, the addition of the small-molecule pifithrin-α limits large deletions, chromosomal translocations, and aneuploidy in a p53-independent manner while maintaining the functionality of CRISPR-engineered T cells, including CAR T cells. Controlling T cell activation and pifithrin-α treatment are easily implementable strategies to improve the genomic integrity of CRISPR-engineered T cells.
    Keywords:  CAR T cell therapy; CRISPR engineering; T cell activation; aneuploidy; chromosomal aberrations; genomic integrity; human T cells; large deletions; pifithrin-alpha; translocations
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101846
  11. Nat Aging. 2024 Dec 05.
    Age-related changes in mammary gland increase tumorigenesis.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00783-0
  12. Front Endocrinol (Lausanne). 2024 ;15 1504405
    Editorial: Chronic stress, telomeres and aging.
    Gabriele Saretzki.
      
    Keywords:  aging; chronic stress; endocrinology; inflammation; telomeres
    DOI:  https://doi.org/10.3389/fendo.2024.1504405
  13. J Clin Invest. 2024 Dec 02. pii: e186520. [Epub ahead of print]134(23):
    Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.
    Nikita L Mani, Samuel E Weinberg.
      Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.
    DOI:  https://doi.org/10.1172/JCI186520
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