bims-imseme 2024-12-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–12–15
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
Nutrient-driven histone code determines exhausted CD8+ T cell fates.
The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.
Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8+ T cells.
Metabolic reprogramming, sensing, and cancer therapy.
Making stronger T cells.
Spermidine alleviates thymopoiesis defects and aging of the peripheral T-cell population in mice after radiation exposure.
Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer.
Unraveling of Phosphotyrosine Signaling Complexes Associated with T Cell Exhaustion Using Multiplex Co-Fractionation/Mass Spectrometry.
DPP4 promotes an immunoenhancing tumor microenvironment through exhausted CD8+ T cells with activating IL13-IL13RA2 axis in papillary thyroid cancer.
GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process.
A metabolic pathway for improving adoptive cellular therapy.
EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.
Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state.
High Extracellular K+ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and Treg Subsets.
Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice.
Lithium Enhances Ferroptosis sensitivity in melanoma cells and promotes CD8+ T Cell infiltration and differentiation.
Central control of dynamic gene circuits governs T cell rest and activation.
IL-23R is a senescence-linked circulating and tissue biomarker of aging.
Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8+ T Cells during JEV Infection.
Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.

Cancer Cell. 2024 Dec 03. pii: S1535-6108(24)00438-0. [Epub ahead of print]

Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.

Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G Chen, Hong Zhu, Philip D Greenberg, Guideng Li.

Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2024.11.003
Science. 2024 Dec 12. eadj3020

Nutrient-driven histone code determines exhausted CD8+ T cell fates.

Shixin Ma, Michael S Dahabieh, Thomas H Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M DeCamp, Brandon M Oswald, Ryan D Sheldon, Abigail E Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G Jones, Susan M Kaech.

Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

DOI: https://doi.org/10.1126/science.adj3020
Discov Immunol. 2024 ;3(1): kyae016

The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.

Michelangelo Certo, Jennifer Niven, Robert Haas, Paula Rudzinska, Joanne Smith, Danilo Cucchi, Jose R Hombrebueno, Claudio Mauro.

   Background: Immunometabolism is a crucial determinant of immune cell function, influencing cellular activation and differentiation through metabolic pathways. The intricate interplay between metabolism and immune responses is highlighted by the distinct metabolic programs utilized by immune cells to support their functions. Of particular interest is the pentose phosphate pathway (PPP), a key metabolic pathway branching out of glycolysis that plays a pivotal role in generating NADPH and pentose sugars crucial for antioxidant defense and biosynthesis. The sedoheptulose kinase Carbohydrate Kinase-like protein (CARKL), an enzyme involved in the PPP, emerges as a critical regulator of cell metabolism and was previously shown to play a role in macrophage function.
Methods: This study delves into the impact of CARKL expression on T-cell functionality, revealing dynamic alterations in response to cellular activation. Notably, CARKL overexpression leads to significant metabolic shifts in T cells, affecting mitochondrial respiration, ATP production, and inflammatory cytokine profiles. Furthermore, CARKL modulation influences T-cell motility by regulating chemokine receptor expression, particularly compromising CXCR3 expression and impairing T-cell migration in response to specific chemokine signals.
Conclusions: These findings underscore the multifaceted role of CARKL as a metabolic regulator shaping T-cell responses. Overall, our data reveal the complex regulatory mechanisms orchestrated by CARKL in T-cell function, with implications for immune regulation. Further exploration of the molecular interactions between CARKL and metabolic reprogramming in T cells could provide valuable insights into immune regulation and potential therapeutic strategies.

Keywords:  CARKL; T cells; immunometabolism; inflammation; pentose phosphate pathway; reprogramming

DOI:  https://doi.org/10.1093/discim/kyae016
Front Immunol. 2024 ;15 1490845

Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8+ T cells.

Qin Tian, Cheng Chen, Jinjin Lu, Xinyu Zheng, Xiuming Zhai, Yanping Yang, Ziyao Zhao, Jiangtao Hao, Ke Yang, Lilin Ye, Yifei Wang.

  During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8+ T cells. Nevertheless, exhausted CD8+ T (TEX) cells still preserve certain effector function, and maintaining a reservoir of exhausted cells is of vital importance for virus elimination and tumor eradiation. Despite considerable work interrogating the rejuvenation of TEX cells, mechanisms underpinning the clonal deletion of TEX cells remain largely unexplored over the past decade. In this study, we employed mouse models of LCMV infection to demonstrate that excessive accumulation of lipid peroxidation rendered virus-specific TEX cells to ferroptosis, which may correlate with enhanced mitochondria-derived oxidative stress and compromised activity of glutathione peroxidase 4 (GPX4). In addition, either incomplete or complete ablation of GPX4 resulted in exacerbated ferroptosis and aggravated shrunken population of virus-specific TEX cells. On the other hand, inhibiting ferroptosis via administration of a ferroptosis inhibitor or overexpression of GPX4 greatly rectified the cell loss of virus-specific TEX cells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific TEX cells and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific TEX cells.

Keywords:  GPX4; LCMV; T cell exhaustion; chronic viral infection; clonal deletion; exhausted CD8+ T cells; ferroptosis; persistence

DOI:  https://doi.org/10.3389/fimmu.2024.1490845
Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064

Metabolic reprogramming, sensing, and cancer therapy.

Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.

  The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy

DOI:  https://doi.org/10.1016/j.celrep.2024.115064
Nat Cell Biol. 2024 Dec;26(12): 2013

Making stronger T cells.

Stylianos Lefkopoulos.

DOI: https://doi.org/10.1038/s41556-024-01577-7
Exp Gerontol. 2024 Dec 04. pii: S0531-5565(24)00292-4. [Epub ahead of print] 112646

Spermidine alleviates thymopoiesis defects and aging of the peripheral T-cell population in mice after radiation exposure.

Kengo Yoshida, Zhenqiu Liu, Yoshiko Kubo, Masahiko Miura, Mika Yamaoka, Hiroko Nagamura, Munechika Misumi, Yoichiro Kusunoki.

  The T cell aging process can be modified by genotoxic factors, including ionizing radiation, and metabolic controls, such as caloric restriction; the former accelerates and the latter retards the process. However, the mechanisms by which these systemic factors interact to cause T cell aging remain unclear. This study investigated the naïve T-cell pool, thymic cellularity, and transcriptome in mice irradiated with 3.8 Gy at 5 weeks of age and treated 13 months later with 30 mM spermidine (SPD), a metabolism regulator. The number of conventional naïve CD4 and CD8 T cells in the peripheral blood decreased 14 months after irradiation whereas the number of virtual memory naïve T cells, which increased with age, further increased by irradiation. However, these radiation-related changes were not significant in similarly irradiated mice that were subsequently treated with SPD. The numbers of total, double-positive, and single-positive thymocytes were decreased by irradiation, whereas none were decreased in the irradiated mice treated with SPD. RNA sequencing of thymus cells revealed 803 upregulated genes in irradiated mice compared with those in non-irradiated control mice, with these genes enriched in leukocyte activation and inflammatory cytokine production. However, only 22 genes were upregulated in irradiated and SPD-treated mice, suggesting a reversal of many radiation-induced gene expression changes. These findings suggest that SPD may alleviate radiation-induced acceleration of T-cell aging, particularly by mitigating reduced thymopoiesis and inflammation. Further research is warranted to explore the rejuvenating potential of SPD and its mechanisms of action in accelerated T-cell aging.

Keywords:  Radiation; Spermidine; T-cell aging

DOI:  https://doi.org/10.1016/j.exger.2024.112646
Cancer Cell. 2024 Dec 09. pii: S1535-6108(24)00440-9. [Epub ahead of print]42(12): 2045-2063.e10

Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer.

Inga-Maria Launonen, Iga Niemiec, María Hincapié-Otero, Erdogan Pekcan Erkan, Ada Junquera, Daria Afenteva, Matias M Falco, Zhihan Liang, Matilda Salko, Foteini Chamchougia, Angela Szabo, Fernando Perez-Villatoro, 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 K Sorger, Anna Vähärautio, Anniina Färkkilä.

  Anti-tumor immunity is crucial for high-grade serous ovarian cancer (HGSC) prognosis, yet its adaptation upon standard chemotherapy remains poorly understood. Here, we conduct spatial and molecular characterization of 117 HGSC samples collected before and after chemotherapy. Our single-cell and spatial analyses reveal increasingly versatile immune cell states forming spatiotemporally dynamic microcommunities. We describe Myelonets, networks of interconnected myeloid cells that contribute to CD8+ T cell exhaustion post-chemotherapy and show that M1/M2 polarization at the tumor-stroma interface is associated with CD8+ T cell exhaustion and exclusion, correlating with poor chemoresponse. Single-cell and spatial transcriptomics reveal prominent myeloid-T cell interactions via NECTIN2-TIGIT induced by chemotherapy. Targeting these interactions using a functional patient-derived immuno-oncology platform demonstrates that high NECTIN2-TIGIT signaling in matched tumors predicts responses to immune checkpoint blockade. Our discovery of clinically relevant myeloid-driven spatial T cell exhaustion unlocks immunotherapeutic strategies to unleash CD8+ T cell-mediated anti-tumor immunity in HGSC.

Keywords:  immuno-oncology; multiomics; ovarian cancer; spatial biology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2024.11.005
Anal Chem. 2024 Dec 11.

Unraveling of Phosphotyrosine Signaling Complexes Associated with T Cell Exhaustion Using Multiplex Co-Fractionation/Mass Spectrometry.

Wei Liu, Hailong Yu, Guoquan Yan, Shun Shen, Mingxia Gao, Xiangmin Zhang.

T cell exhaustion, characterized by the upregulation of inhibitory receptors and loss of effector functions, plays a crucial role in tumor immune evasion. This study utilizes a high-throughput, reproducible, and robust integrated ion-exchange chromatography-tandem mass tag (IEC-TMT) platform, coupled with a complex-centric quantification algorithm, to thoroughly profile phosphotyrosine (pTyr) protein complex changes during T cell exhaustion. The platform's high reproducibility is evidenced by >0.94 correlation and a median coefficient of variation of 0.25 among quantified complexes in HeLa cell biological replicates. This high-throughput approach allowed analysis of 312 fractions within 2 days, identifying 268 pTyr protein complexes from the T cell exhaustion model. Robust quantification of 28 complexes revealed 12 exhibiting significant abundance alterations in exhausted T cells, notably impacting lysosomal and endoplasmic reticulum-associated complexes. RTN4, a subunit of the newly identified PPI204 protein complex, is upregulated in exhausted T cells. Its knockdown reversed T cell exhaustion, enhancing antitumor immunity. These findings provide novel insights into the molecular mechanisms of T cell exhaustion and propose RTN4 as a potential therapeutic target.

DOI: https://doi.org/10.1021/acs.analchem.4c04179
Int Immunopharmacol. 2024 Dec 10. pii: S1567-5769(24)02282-3. [Epub ahead of print]145 113760

DPP4 promotes an immunoenhancing tumor microenvironment through exhausted CD8+ T cells with activating IL13-IL13RA2 axis in papillary thyroid cancer.

Ren Jing, Nan Wu, Qian Zhang, Jinlin Liu, Ying Zhao, Shan Zeng, Shaojie Wu, Yang Wu, Shijian Yi.

   BACKGROUND: Papillary thyroid cancer (PTC) is among the most prevalent forms of endocrine malignancy with a rapid rise in incidence rates worldwide; however, the composition and characteristics of its immune microenvironment is poorly understand. Here, this work investigated the precise function of Dipeptidyl peptidase 4 (DPP4) in tumor-infiltrated T cells within PTC by investigating its role in cytokine-mediated signaling pathways.
METHODS: TCGA and GEO data as well as human PTC specimens confirmed the expression of DPP4 in PTC. The CIBERSORT and TIMER tool were used to analyze the distribution of tumor-infiltrating immune cells in PTC. CD8+ T cells from PTC patient's peripheral blood were cultured and used in a three-dimensional model for direct co-culture with PTC tumors to investigate DPP4 function.
RESULTS: Bioinformatic analyses has uncovered a significant upregulation of DPP4, which enhances the survival and migration of PTC cells in vitro. DPP4 upregulation significantly correlated with advanced grades, stages, and poor progression-free survival. DPP4 influences immune function and the exhaustion of CD8+ T cells through the IL13-IL13RA2 axis. The inhibition of DPP4 reduces CD8+ T cell exhaustion and IL13 secretion, while also blocking the IL13-IL13RA2 axis, thereby promoting the mesenchymal-to-epithelial transition of PTC cells.
CONCLUSION: Blocking DPP4 leads to the conversion of exhausted CD8+ T cells with decreased IL13 level, resulting in downregulation of IL13RA2 to promote mesenchymal-to-epithelial transition of PTC cells. This highlights DPP4 as a potential therapeutic target, particularly between CD8+ T cells and PTC cells via IL13-IL13RA2 axis, and represents a novel avenue for combined immunotherapy in PTC.

Keywords:  DPP4; IL13-IL13RA2 axis; Mesenchymal-to-epithelial transition; Papillary thyroid cancer; T cell exhaustion

DOI:  https://doi.org/10.1016/j.intimp.2024.113760
Biogerontology. 2024 Dec 06. 26(1): 19

GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process.

Antero Salminen.

  The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging. In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process. GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of MDSCs, Tregs, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.

Keywords:  Ageing; Epigenetics; Immunosenescence; Immunosuppression; Integrated stress response

DOI:  https://doi.org/10.1007/s10522-024-10164-0
Cancer Cell. 2024 Dec 10. pii: S1535-6108(24)00449-5. [Epub ahead of print]

A metabolic pathway for improving adoptive cellular therapy.

Christina M Scheffler, Paul A Beavis, Phillip K Darcy.

In this issue of Cancer Cell, Qiu et al. use single-cell metabolic analysis to identify reduced mannose metabolism as a previously unknown feature of exhausted T cells. This metabolic pathway can be targeted to enhance memory and persistence of adoptively transferred T cells, resulting in improved anti-tumor efficacy.

DOI: https://doi.org/10.1016/j.ccell.2024.11.014
Cancer Cell. 2024 Nov 30. pii: S1535-6108(24)00441-0. [Epub ahead of print]

EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.

Yusuke Isshiki, Xi Chen, Matt Teater, Ioannis Karagiannidis, Henna Nam, Winson Cai, Cem Meydan, Min Xia, Hao Shen, Johana Gutierrez, Vigneshwari Easwar Kumar, Sebastián E Carrasco, Madhu M Ouseph, Samuel Yamshon, Peter Martin, Ofir Griess, Efrat Shema, Patrizia Porazzi, Marco Ruella, Renier J Brentjens, Giorgio Inghirami, Roberta Zappasodi, Amy Chadburn, Ari M Melnick, Wendy Béguelin.

  T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.

Keywords:  CAR-T; DLBCL; EZH2; T cell immunotherapy; bispecific antibodies; follicular lymphoma

DOI:  https://doi.org/10.1016/j.ccell.2024.11.006
bioRxiv. 2024 Nov 27. pii: 2024.11.25.625252. [Epub ahead of print]

Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.

Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
Key Points: Age-related attrition of the megakaryocytic niche and associated PF4 downregulation is a central mechanism in HSC aging.PF4 supplementation, acting on LDLR and CXCR3 receptors, rejuvenates the function of aged HSCs.

DOI: https://doi.org/10.1101/2024.11.25.625252
Cell Rep Med. 2024 Dec 04. pii: S2666-3791(24)00640-2. [Epub ahead of print] 101869

Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state.

Xingying Zhang, Chenze Zhang, Shan Lu, Jingxi Dong, Na Tang, Yao Wang, Weidong Han, Xi Pan, Xiang Zhang, Duan Liu, Ng Shyh-Chang, Yu Wang, Guihai Feng, Haoyi Wang.

  T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.

Keywords:  T cell exhaustion; glycolytic metabolism; high-throughput drug screening; immunotherapy for solid tumors; miltefosine

DOI:  https://doi.org/10.1016/j.xcrm.2024.101869
Eur J Immunol. 2024 Dec 09. e202451440

High Extracellular K+ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and Treg Subsets.

Brandon Han Siang Wong, Zhi Sheng Poh, James Tan Chia Wei, Kottaiswamy Amuthavalli, Ying Swan Ho, Shuwen Chen, Shi Ya Mak, Xuezhi Bi, Richard D Webster, Vishalkumar G Shelat, K George Chandy, Navin Kumar Verma.

  Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME.

Keywords:  T‐cell exhaustion; T‐lymphocytes; immune suppression; metabolomics

DOI:  https://doi.org/10.1002/eji.202451440
bioRxiv. 2024 Nov 25. pii: 2024.11.25.625088. [Epub ahead of print]

Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice.

Seung-Chul Choi, Yong Ge, Milind V Joshi, Damian Jimenez, Lauren T Padilla, Cassandra LaPlante, Jeffery C Rathmell, Mansour Mohamadzadeh, Laurence Morel.

Glutamine metabolism is essential for T cell activation and functions. The inhibition of glutaminolysis impairs Th17 cell differentiation and alters Th1 cell functions. There is evidence for an active glutaminolysis in the immune cells of lupus patients. Treatment of lupus-prone mice with glutaminolysis inhibitors ameliorated disease in association with a reduced frequency of Th17 cells. This study was performed to determine the role of glutaminolysis in murine Tfh cells, a critical subset of helper CD4 + T cells in lupus that provide help to autoreactive B cells to produce autoantibodies. We showed that lupus Tfh present a high level of glutamine metabolism. The pharmacological inhibition of glutaminolysis with DON had little effect on the Tfh cells of healthy mice, but it reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production, germinal center B cell dynamics, as well as a reduction of the frequency of atypical age-related B cells and plasma cells. Accordingly, profound transcriptomic and metabolic changes, including an inhibition of glycolysis, were induced in lupus Tfh cells by DON, while healthy Tfh cells showed little changes. The T cell-specific inhibition of glutaminolysis by deletion of the gene encoding for the glutaminase enzyme GLS1 largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with little effect in a congenic control background. These results were confirmed in an induced model of lupus. Finally, we showed that T cell-specific Gls1 deletion impaired T- dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results demonstrated a greater intrinsic requirement of lupus Tfh cells for their helper functions, and they suggest that targeting glutaminolysis may be beneficial to treat lupus.

DOI: https://doi.org/10.1101/2024.11.25.625088
Free Radic Biol Med. 2024 Dec 05. pii: S0891-5849(24)01110-9. [Epub ahead of print]227 233-245

Lithium Enhances Ferroptosis sensitivity in melanoma cells and promotes CD8+ T Cell infiltration and differentiation.

Bo Zhu, Chunhao Yang, Siqi Hua, Kaiqiang Li, Pengyou Shang, Xiao Chen, Zi-Chun Hua.

  Lithium exposure reduces melanoma incidence and mortality, yet its therapeutic mechanisms are unclear. This study explores the effects of lithium on ferroptosis sensitivity and anti-tumor T cell response in melanoma. We found that lithium significantly enhanced RSL3-induced ferroptosis in vitro, evidenced by increased mitochondrial peroxide, lipid peroxidation, and mitochondrial abnormalities. Lithium also inhibited B16-F10 melanoma cell proliferation and migration in a dose-dependent manner. Cell cycle analysis showed lithium and RSL3 induced distinct perturbations, including G2/M and G0/G1 phase arrests. Mechanistically, lithium influenced intracellular ferrous ion levels by downregulating ferritin heavy chain (Fth1), crucial for iron homeostasis. The combination of lithium and RSL3 significantly suppressed tumor growth in mice, correlating with reduced Fth1 expression and increased iron deposition in the spleen and liver, highlighting a novel interaction between lithium and iron metabolism. Additionally, this combination enhanced CD8+ T cell infiltration and IFN-γ expression in the tumor microenvironment, especially among cytotoxic effector CD8+ T cells. These findings reveal the pro-ferroptotic and immune regulation roles of lithium, broaden our understanding of its biological roles, and propose new strategies for ferroptosis-targeted therapies in melanoma.

Keywords:  Ferritin heavy chain; Ferroptosis; Iron homeostasis; Lithium; Melanoma; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.012
Nature. 2024 Dec 11.

Central control of dynamic gene circuits governs T cell rest and activation.

Maya M Arce, Jennifer M Umhoefer, Nadia Arang, Sivakanthan Kasinathan, Jacob W Freimer, Zachary Steinhart, Haolin Shen, Minh T N Pham, Mineto Ota, Anika Wadhera, Rama Dajani, Dmytro Dorovskyi, Yan Yi Chen, Qi Liu, Yuan Zhou, Danielle L Swaney, Kirsten Obernier, Brian R Shy, Julia Carnevale, Ansuman T Satpathy, Nevan J Krogan, Jonathan K Pritchard, Alexander Marson.

The ability of cells to maintain distinct identities and respond to transient environmental signals requires tightly controlled regulation of gene networks1-3. These dynamic regulatory circuits that respond to extracellular cues in primary human cells remain poorly defined. The need for context-dependent regulation is prominent in T cells, where distinct lineages must respond to diverse signals to mount effective immune responses and maintain homeostasis4-8. Here we performed CRISPR screens in multiple primary human CD4+ T cell contexts to identify regulators that control expression of IL-2Rα, a canonical marker of T cell activation transiently expressed by pro-inflammatory effector T cells and constitutively expressed by anti-inflammatory regulatory T cells where it is required for fitness9-11. Approximately 90% of identified regulators of IL-2Rα had effects that varied across cell types and/or stimulation states, including a subset that even had opposite effects across conditions. Using single-cell transcriptomics after pooled perturbation of context-specific screen hits, we characterized specific factors as regulators of overall rest or activation and constructed state-specific regulatory networks. MED12 - a component of the Mediator complex - serves as a dynamic orchestrator of key regulators, controlling expression of distinct sets of regulators in different T cell contexts. Immunoprecipitation-mass spectrometry revealed that MED12 interacts with the histone methylating COMPASS complex. MED12 was required for histone methylation and expression of genes encoding key context-specific regulators, including the rest maintenance factor KLF2 and the versatile regulator MYC. CRISPR ablation of MED12 blunted the cell-state transitions between rest and activation and protected from activation-induced cell death. Overall, this work leverages CRISPR screens performed across conditions to define dynamic gene circuits required to establish resting and activated T cell states.

DOI: https://doi.org/10.1038/s41586-024-08314-y
Nat Aging. 2024 Dec 10.

IL-23R is a senescence-linked circulating and tissue biomarker of aging.

Chase M Carver, Sonia L Rodriguez, Elizabeth J Atkinson, Andrew J Dosch, Niels C Asmussen, Paul T Gomez, Ethan A Leitschuh, Jair M Espindola-Netto, Karthik B Jeganathan, Madison G Whaley, Theodore M Kamenecka, Darren J Baker, Andrew J Haak, Nathan K LeBrasseur, Marissa J Schafer.

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

DOI: https://doi.org/10.1038/s43587-024-00752-7
Int J Biol Sci. 2024 ;20(15): 5959-5978

Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8+ T Cells during JEV Infection.

Weijia Zhang, Qing Yu, Xiaochen Gao, Haowei Chen, Jie Su, Yanru Chen, Yanling Li, Nan Zhang, Zhenfang Fu, Min Cui.

  Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), is a mosquito-borne zoonotic disease and a leading cause of viral encephalitis worldwide. While JEV has the ability to traverse the blood-brain barrier (BBB), the precise mechanisms by which it inhibits the immune response prior to penetrating the BBB remain unclear, presenting obstacles in the development of efficacious therapeutic interventions. This study investigated the impact of JEV on CD8+ T cell responses, with a particular focus on the dysfunction of CD8+ T cells during JEV infection. Our results demonstrated that JEV infection significantly elevated the expression of PD-1 and TIM-3 on CD8+ T cells, which are markers of T cell exhaustion, leading to inhibited function and impaired differentiation, resulting in a poorer prognosis in mice. Compared with nondiseased mice, symptomatic mice presented a greater proportion of exhaustion-like CD8+ T cells. In vitro experiments further demonstrated that MDSCs induced an exhaustion-like state in CD8+ T cells, characterized by significant upregulation of PD-1 and TIM-3 expression. Notably, blocking TIM-3 or depleting MDSCs restored CD8+ T cell functionality by rescuing the expression of IFN-γ and TNF-α. Furthermore, the depletion of MDSCs not only alleviated T cell exhaustion-like phenotypes but also improved survival rates in JEV-infected mice. These findings suggest that JEV promotes immune evasion through MDSC-induced CD8+ T cell exhaustion-like states and identify TIM-3 as a promising therapeutic target for JE treatment.

Keywords:  CD8+ T cells; Japanese encephalitis virus; MDSCs; PD-1; TIM-3

DOI:  https://doi.org/10.7150/ijbs.102372
Nat Rev Drug Discov. 2024 Dec 12.

Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.

Sébastien Viel, Eric Vivier, Thierry Walzer, Antoine Marçais.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

DOI: https://doi.org/10.1038/s41573-024-01098-w