bims-imseme 2023-01-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–01–15
twenty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Manipulating T-cell metabolism to enhance immunotherapy in solid tumor.
Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.
Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults.
GOT1 regulates CD8+ effector and memory T cell generation.
Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer.
Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.
Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age.
Soluble and Immobilized Anti-CD3/28 Distinctively Expand and Differentiate Primary Human T Cells: An Implication for Adoptive T Cell Therapy.
Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling.
The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.
Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.
A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.
Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.
Effects of lactate on metabolism and differentiation of CD4+T cells.
Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages.
The poly(C)-binding protein Pcbp2 is essential for CD4+ T cell activation and proliferation.
Metabolites as signalling molecules.
Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.
Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.

Front Immunol. 2022 ;13 1090429

Manipulating T-cell metabolism to enhance immunotherapy in solid tumor.

Chen Chen, Zehua Wang, Yi Ding, Yanru Qin.

  Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.

Keywords:  T cell; adoptive cell therapy; immune checkpoint inhibitor; metabolism reprogramming; oncolytic virus therapy; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2022.1090429
Immunity. 2023 Jan 10. pii: S1074-7613(22)00644-6. [Epub ahead of print]56(1): 32-42

Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.

Jaeoh Park, Pei-Chun Hsueh, Zhiyu Li, Ping-Chih Ho.

The metabolic stress occurring in the tumor microenvironment (TME) hampers T cell anti-tumor immunity by disturbing T cell metabolic and epigenetic programs. Recent studies are making headway toward identifying strategies to unleash T cell activities by targeting T cell metabolism. Furthermore, efforts have been made to improve the efficacy of immune checkpoint blockade and adoptive cell transfer therapies. However, distinct treatment outcomes across different cancers raise the question of whether our understanding of the features of CD8+ T cells within the TME are universal, regardless of their tissue of origin. Here, we review the common and distinct environmental factors affecting CD8+ T cells across tumors. Moreover, we discuss how distinct tissue-specific niches are interpreted by CD8+ T cells based on studies on tissue-resident memory T (Trm) cells and how these insights can pave the way for a better understanding of the metabolic regulation of CD8+ T cell differentiation and anti-tumor immunity.

DOI: https://doi.org/10.1016/j.immuni.2022.12.008
Cells. 2022 Dec 22. pii: 44. [Epub ahead of print]12(1):

Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults.

Ilaria Buondonno, Francesca Sassi, Francesco Cattaneo, Patrizia D'Amelio.

  Aging is associated with changes in the immune system, increased inflammation and mitochondrial dysfunction. The relationship between these phenomena and the clinical phenotype of frailty is unclear. Here, we evaluated the immune phenotypes, T cell functions and mitochondrial functions of immune cells in frail and robust older subjects. We enrolled 20 frail subjects age- and gender-matched with 20 robust controls, and T cell phenotype, response to immune stimulation, cytokine production and immune cell mitochondrial function were assessed. Our results showed that numbers of CD4+ and CD8+ T cells were decreased in frail subjects, without impairment to their ratios. Memory and naïve T cells were not significantly affected by frailty, whereas the expression of CD28 but not that of ICOS was decreased in T cells from frail subjects. T cells from robust subjects produced more IL-17 after CD28 stimulation. Levels of serum cytokines were similar in frail subjects and controls. Mitochondrial bioenergetics and ATP levels were significantly lower in immune cells from frail subjects. In conclusion, we suggest that changes in T cell profiles are associated with aging rather than with frailty syndrome; however, changes in T cell response to immune stimuli and reduced mitochondrial activity in immune cells may be considered hallmarks of frailty.

Keywords:  T cells; aging; cytokine; frailty; immunosenescence; inflammaging; mitochondria

DOI:  https://doi.org/10.3390/cells12010044
Cell Rep. 2023 Jan 12. pii: S2211-1247(22)01891-5. [Epub ahead of print]42(1): 111987

GOT1 regulates CD8+ effector and memory T cell generation.

Wei Xu, Chirag H Patel, Liang Zhao, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Rachel S Helms, Jiayu Wen, Jonathan D Powell.

  T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.

Keywords:  CP: Metabolism; GOT1; HIF; NADH/NAD; effector and memory CD8(+) T cell; glucose; glutamate; serine

DOI:  https://doi.org/10.1016/j.celrep.2022.111987
Iran Biomed J. 2023 Dec 19. pii: A-10-5091-1. [Epub ahead of print]

Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer.

Jahangir Abdesheikhi, Farnaz Sedghy, Merat Mahmoodi, Hossein Fallah, Mahdi Ranjkesh.

Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events affecting the function of immune cells leads to new therapeutic opportunities for the treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathways, such as glycolysis, TCA cycle, and fatty acid metabolism, affect significantly the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.

Keywords: cancer metabolism; immunometabolism; metabolic pathways
Sci Immunol. 2023 Jan 13. 8(79): eabq0178

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.

Kelsey Voss, Allison E Sewell, Evan S Krystofiak, Katherine N Gibson-Corley, Arissa C Young, Jacob H Basham, Ayaka Sugiura, Emily N Arner, William N Beavers, Dillon E Kunkle, Megan E Dickson, Gabriel A Needle, Eric P Skaar, W Kimryn Rathmell, Michelle J Ormseth, Amy S Major, Jeffrey C Rathmell.

T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for TH1 and inhibitory for induced regulatory T cells (iTregs). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited TH1 and TH17 cells yet enhanced iTregs. In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on TH17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.

DOI: https://doi.org/10.1126/sciimmunol.abq0178
Aging Cell. 2023 Jan 13. e13767

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age.

Md Torikul Islam, Eric Tuday, Shanena Allen, John Kim, Daniel W Trott, William L Holland, Anthony J Donato, Lisa A Lesniewski.

  Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose (p = 0.001) and glucose tolerance (p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs (p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance (p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

Keywords:  aging; dasatinib; immune cells; inflammation; metabolic function; quercetin; senescence; senolytics

DOI:  https://doi.org/10.1111/acel.13767
Iran J Allergy Asthma Immunol. 2022 Dec 24. 21(6): 630-637

Soluble and Immobilized Anti-CD3/28 Distinctively Expand and Differentiate Primary Human T Cells: An Implication for Adoptive T Cell Therapy.

Tahereh Soltantoye, Behnia Akbari, Hamid Reza Mirzaei, Jamshid Hadjati.

  Cell-based cancer therapies have led to a paradigm shift in the treatment of patients with various cancers. To date, a vast majority of cancer immunotherapies have used genetically engineered T cells to target tumors. Stimulation and ex vivo expansion of T cells, as one of the crucial starting materials for T cell manufacturing, have always been a critical part of adoptive T-cell therapy (ACT). Typically, anti-CD3 and anti-CD28 monoclonal antibodies (mAbs) along with interleukin-2 (IL-2), through transducing signals one, two, and three, respectively, are essential for in vitro T cell activation. Terminal differentiation and replicative senescence are the main barriers of the ACTs during the manufacturing of engineered T cells ex vivo.In this study, we aimed to compare the T cell activation protocol that we developed in our lab (soluble anti-CD3/28 mAbs) with a common T cell activation protocol (immobilized anti-CD3/soluble anti-CD28) in terms of T cell expansion, activation, immunophenotype, and cellular fate. We observed that T cells were equally expanded in both protocols. Notably, our modified protocol promoted the outgrowth of CD8+ T cells postactivation. Concerning the low concentrations of both soluble anti-CD3 and anti-CD28, the modified protocol could significantly enrich memory T cell subsets. In conclusion, our data demonstrated that the soluble CD3/28 mAbs protocol is cost-effective and more efficient for generating more potent T cells, thereby expecting a better therapeutic outcome.

Keywords:  Adoptive cellular therapy; Immobilized antibodies; Lymphocyte activation; Memory phenotype

DOI:  https://doi.org/10.18502/ijaai.v21i6.11521
Nat Commun. 2023 Jan 11. 14(1): 156

Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling.

Jina Yun, Simon Hansen, Otto Morris, David T Madden, Clare Peters Libeu, Arjun J Kumar, Cameron Wehrfritz, Aaron H Nile, Yingnan Zhang, Lijuan Zhou, Yuxin Liang, Zora Modrusan, Michelle B Chen, Christopher C Overall, David Garfield, Judith Campisi, Birgit Schilling, Rami N Hannoush, Heinrich Jasper.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation. We identify the secreted N-terminal domain of Ptk7 as a key component of the SASP that activates non-canonical Wnt / Ca2+ signaling through FZD7 in intestinal stem cells (ISCs). Changes in cytosolic [Ca2+] elicited by Ptk7 promote nuclear translocation of YAP and induce expression of YAP/TEAD target genes, impairing symmetry breaking and stem cell differentiation. Our study discovers secreted Ptk7 as a factor released by senescent cells and provides insight into the mechanism by which cellular senescence contributes to tissue dysfunction in aging and disease.

DOI: https://doi.org/10.1038/s41467-022-35487-9
Cell Rep. 2023 Jan 04. pii: S2211-1247(22)01867-8. [Epub ahead of print]42(1): 111963

The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.

Joseph W Dean, Eric Y Helm, Zheng Fu, Lifeng Xiong, Na Sun, Kristen N Oliff, Marcus Muehlbauer, Dorina Avram, Liang Zhou.

  The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ T cells; however, its cell-intrinsic role in CD8+ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ T cells leads to increased CD127-KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ T cells also highly express AHR that regulates in vitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity.

Keywords:  CD8(+) T cell; CP: Immunology; aryl hydrocarbon receptor; cancer immunology; cytotoxicity; development; differentiation; mucosal immunology; tissue resident memory; tumor infiltrating lymphocyte

DOI:  https://doi.org/10.1016/j.celrep.2022.111963
Aging Cell. 2023 Jan 10. e13764

Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.

Nika Rajabian, Debanik Choudhury, Izuagie Ikhapoh, Shilpashree Saha, Aishwarya S Kalyankar, Pihu Mehrotra, Aref Shahini, Kendall Breed, Stelios T Andreadis.

  Cellular senescence leads to the depletion of myogenic progenitors and decreased regenerative capacity. We show that the small molecule 2,6-disubstituted purine, reversine, can improve some well-known hallmarks of cellular aging in senescent myoblast cells. Reversine reactivated autophagy and insulin signaling pathway via upregulation of Adenosine Monophosphate-activated protein kinase (AMPK) and Akt2, restoring insulin sensitivity and glucose uptake in senescent cells. Reversine also restored the loss of connectivity of glycolysis to the TCA cycle, thus restoring dysfunctional mitochondria and the impaired myogenic differentiation potential of senescent myoblasts. Altogether, our data suggest that cellular senescence can be reversed by treatment with a single small molecule without employing genetic reprogramming technologies.

Keywords:  aging; cellular senescence; metabolism; methionine pathway; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13764
Nat Commun. 2023 Jan 06. 14(1): 98

A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.

Sandra Tietscher, Johanna Wagner, Tobias Anzeneder, Claus Langwieder, Martin Rees, Bettina Sobottka, Natalie de Souza, Bernd Bodenmiller.

Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments.

DOI: https://doi.org/10.1038/s41467-022-35238-w
Cell. 2023 Jan 05. pii: S0092-8674(22)01520-3. [Epub ahead of print]186(1): 63-79.e21

Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.

Clara Correia-Melo, Stephan Kamrad, Roland Tengölics, Christoph B Messner, Pauline Trebulle, StJohn Townsend, Sreejith Jayasree Varma, Anja Freiwald, Benjamin M Heineike, Kate Campbell, Lucía Herrera-Dominguez, Simran Kaur Aulakh, Lukasz Szyrwiel, Jason S L Yu, Aleksej Zelezniak, Vadim Demichev, Michael Mülleder, Balázs Papp, Mohammad Tauqeer Alam, Markus Ralser.

  Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.

Keywords:  chronological aging; eukaryotic longevity; metabolic microenvironment; metabolite exchange interactions

DOI:  https://doi.org/10.1016/j.cell.2022.12.007
Cancer Cell. 2023 Jan 03. pii: S1535-6108(22)00594-3. [Epub ahead of print]

Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.

Gaopeng Li, Jae Eun Choi, Ilona Kryczek, Yilun Sun, Peng Liao, Shasha Li, Shuang Wei, Sara Grove, Linda Vatan, Reagan Nelson, Grace Schaefer, Steven G Allen, Kamya Sankar, Leslie A Fecher, Mishal Mendiratta-Lala, Timothy L Frankel, Angel Qin, Jessica J Waninger, Alangoya Tezel, Ajjai Alva, Christopher D Lao, Nithya Ramnath, Marcin Cieslik, Paul W Harms, Michael D Green, Arul M Chinnaiyan, Weiping Zou.

  Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.

Keywords:  FGF2; IFNγ; PD-L1/PD-1 pathway; T cell immunity; complete response; glycolytic metabolism; hyperprogressive disease; immune checkpoint blockade; oncogenesis; β-catenin

DOI:  https://doi.org/10.1016/j.ccell.2022.12.008
Diabetes Metab J. 2023 Jan 12.

The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.

Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee.

  Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.

Keywords:  Metabolic diseases; Mitochondria; Muscular atrophy; Pyruvate dehydrogenase acetyl-transferring kinase; Pyruvate dehydrogenase complex; Sarcopenia

DOI:  https://doi.org/10.4093/dmj.2022.0305
Mol Immunol. 2023 Jan 06. pii: S0161-5890(22)00505-3. [Epub ahead of print]154 96-107

Effects of lactate on metabolism and differentiation of CD4+T cells.

Yu-Ting Zhang, Mu-Lan Xing, Hui-Hua Fang, Wei-Dong Li, Li Wu, Zhi-Peng Chen.

   BACKGROUND: Lactate accumulation caused by abnormal tumor metabolism can induce the formation of an inhibitory immune microenvironment through a variety of pathways, which is characterized by regulatory T cells (Treg) infiltration and effector T cells (Teff) depletion. Studies have found that the key reason why Treg cells can survive in harsh environments lies in their flexible metabolic mode, which can use lactate in tumor microenvironment (TME) as an alternative energy substance to maintain their inhibitory activity. In addition, lactate could also promote the differentiation of CD4+T cells into Treg, but the mechanism was not completely clear. The purpose of this study was to investigate the possible mechanism by which lactate is utilized by CD4+T cells to influence Th17/Treg ratio.
METHODS: Basal cytokines (anti-CD3, anti-CD28, TGF-β) and 10 mM lactate was added into Naïve CD4+T cells basal medium for 3 days. After TCR stimulation, Naïve CD4+T converted to CD4+T. Flow cytometry was used to detect the proportion of Treg cells; ELISA was used to detect the activity of LDHA, LDHB and NADH and the amount of α -Ketoglutaric Acid (α-KG) and 2-Hydroxyglutaric Acid (2HG) after lactate entered the cells; Western Blot and RT-PCR were used to detect the protein and gene expression of Foxp3, RORγt, LDHA and LDHB. In the validation experiment, lactate uptake inhibitor AZD3965, LDHA inhibitor GSK2837808A and NADH conversion inhibitor Rotenone were added respectively to observe the differentiation ratio of Treg cells and confirm the key points of metabolism; the degradation of Treg cell transcription factor Foxp3 was interfered with ubiquitination inhibitors to observe whether it co-ubiquitinated with HIF-1α; the expression and activity of LDHA, LDHB and NADH in mitochondria and cytoplasm were detected to confirm cell localization.
RESULTS: When basal cytokines (anti-CD3, anti-CD28, TGF-β) stimulated, lactate was added to the culture medium, and CD4+T cells absorbed a large amount of lactate not only through MCT1 (monocarboxylic acid transporter), but also increased the expression of lactate dehydrogenase and accelerated the intracellular metabolism of lactate. LDHB in cytoplasm mainly catalyzed the dehydrogenation of lactate to pyruvate, accompanied by the transformation reaction between NAD+ and NADH. The latter further entered the mitochondria and participates in the tricarboxylic acid cycle metabolism. In addition, lactate could significantly increase the level of LDHA in mitochondria and promote the transformation of α-KG to 2HG, accompanied by the transformation of NADH to NAD+. These metabolic changes eventually led to an increase in the intracellular 2HG/α-KG ratio. Abnormal 2HG increased the proportion of Treg by inhibiting ATP5B-mediated phosphorylation of mTOR and the synthesis of HIF-1α, causing it not be enough to ubiquitinate and degrade with Foxp3.
CONCLUSIONS: Lactate plays an important role in regulating the differentiation of Treg cells, inducing the expression and function of LDHA and promoting the transformation of α-KG to 2HG may be an important mechanism.

Keywords:  LDHA; Lactate; NADH; Th17; Treg

DOI:  https://doi.org/10.1016/j.molimm.2022.12.015
Immunity. 2023 Jan 10. pii: S1074-7613(22)00642-2. [Epub ahead of print]56(1): 162-179.e6

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages.

Mélanie Tichet, Stephan Wullschleger, Agnieszka Chryplewicz, Nadine Fournier, Rachel Marcone, Annamaria Kauzlaric, Krisztian Homicsko, Laura Codarri Deak, Pablo Umaña, Christian Klein, Douglas Hanahan.

  Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1+ T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8+ T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.

Keywords:  bispecific therapeutic antibody; cancer immunotherapy; high endothelial venule; immunocytokine; mouse model of human cancer; reprogramming macrophages; resistance to immunotherapies; stem-like T cells; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2022.12.006
iScience. 2023 Jan 20. 26(1): 105860

The poly(C)-binding protein Pcbp2 is essential for CD4+ T cell activation and proliferation.

Massimo Martinelli, Gabrielle Aguilar, David S M Lee, Andrew Kromer, Nhu Nguyen, Benjamin J Wilkins, Tatiana Akimova, Ulf H Beier, Louis R Ghanem.

  The RNA-binding protein Pcbp2 is widely expressed in the innate and adaptive immune systems and is essential for mouse development. To determine whether Pcbp2 is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for T conventional cell (Tconv) proliferation, working through regulation of co-stimulatory signaling. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system.

Keywords:  Cell biology; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.105860
Nat Rev Mol Cell Biol. 2023 Jan 12.

Metabolites as signalling molecules.

Steven Andrew Baker, Jared Rutter.

Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.

DOI: https://doi.org/10.1038/s41580-022-00572-w
Sci Adv. 2023 Jan 13. 9(2): eadd5163

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.

Helena A K Lapatto, Minna Kuusela, Aino Heikkinen, Maheswary Muniandy, Birgitta W van der Kolk, Swetha Gopalakrishnan, Noora Pöllänen, Martin Sandvik, Mark S Schmidt, Sini Heinonen, Sina Saari, Juho Kuula, Antti Hakkarainen, Janne Tampio, Tuure Saarinen, Marja-Riitta Taskinen, Nina Lundbom, Per-Henrik Groop, Marja Tiirola, Pekka Katajisto, Marko Lehtonen, Charles Brenner, Jaakko Kaprio, Satu Pekkala, Miina Ollikainen, Kirsi H Pietiläinen, Eija Pirinen.

Nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)-discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD+ metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.

DOI: https://doi.org/10.1126/sciadv.add5163
Cell Rep. 2023 Jan 09. pii: S2211-1247(22)01842-3. [Epub ahead of print]42(1): 111941

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.

Allison K Meyers, Zhan Wang, Wenzheng Han, Qingxia Zhao, Manal Zabalawi, Likun Duan, Juan Liu, Qianyi Zhang, Rajesh K Manne, Felipe Lorenzo, Matthew A Quinn, Qianqian Song, Daping Fan, Hui-Kuan Lin, Cristina M Furdui, Jason W Locasale, Charles E McCall, Xuewei Zhu.

  Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggestsa non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.

Keywords:  CP: Immunology; NLRP3 inflammasome; autophagy; cristae; immunometabolism; macrophages; metabolic flux; mitochondria; mitochondrial fission and fusion; pyruvate dehydrogenase kinase; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2022.111941