bims-imicid 2024-09-29 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–09–29
eightteen papers selected by
Dylan Ryan, University of Cambridge

Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.
Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders.
Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.
Metabolic reprogramming of macrophages in cancer therapy.
Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
Innate immunity champions: The diverse functions of macrophages.
Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
Mitochondrial metabolism regulated macrophage phenotype in myocardial infarction.
Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.
Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.
Toxoplasma acyl-CoA synthetase TgACS3 is crucial to channel host fatty acids in lipid droplets and for parasite propagation.
Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape.
Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells.
Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.
Phages reconstitute NAD+ to counter bacterial immunity.
The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780

Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.

Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.

  Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.

Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2024.114780
Cell Metab. 2024 Sep 17. pii: S1550-4131(24)00362-0. [Epub ahead of print]

Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.

Xiaoli Wei, Dongqing Wu, Jing Li, Miaomiao Wu, Qianhui Li, Zhaodi Che, Xu Cheng, Qianying Cheng, Fan Yin, Hao Zhang, Xuefu Wang, Shabnam Abtahi, Li Zuo, Lei Hang, Lili Ma, Wei-Ting Kuo, Xiaoying Liu, Jerrold R Turner, Hua Wang, Jia Xiao, Fei Wang.

  Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

Keywords:  IRG1; MASLD; itaconate; macrophage polarization; metabolic reprogramming; β-arrestin 2

DOI:  https://doi.org/10.1016/j.cmet.2024.08.010
Biochim Biophys Acta Mol Basis Dis. 2024 Sep 20. pii: S0925-4439(24)00518-0. [Epub ahead of print]1871(1): 167524

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders.

Sanne G S Verberk, Nico Hahn, Daan Heister, Jorien Haverkamp, Khya S Snelder, Kyra E de Goede, Friederieke S Gorki, Jerome J A Hendriks, Riekelt H Houtkooper, Gepke Visser, Barbara Sjouke, Mirjam Langeveld, Jan Van den Bossche.

  Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

Keywords:  Fatty acid oxidation disorders; Immunometabolism; Immunophenotyping; Inflammation; Macrophages

DOI:  https://doi.org/10.1016/j.bbadis.2024.167524
Nat Rev Cardiol. 2024 Sep 20.

Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.

Fabrizia Bonacina, Xiangyu Zhang, Nicolas Manel, Laurent Yvan-Charvet, Babak Razani, Giuseppe D Norata.

Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.

DOI: https://doi.org/10.1038/s41569-024-01072-4
Trends Endocrinol Metab. 2024 Sep 19. pii: S1043-2760(24)00244-3. [Epub ahead of print]

Metabolic reprogramming of macrophages in cancer therapy.

Xudong Wang, Shaolong Zhang, Dixuan Xue, Dante Neculai, Jin Zhang.

  Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.

Keywords:  cancer therapy; macrophage; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tem.2024.08.009
Res Sq. 2024 Sep 16. pii: rs.3.rs-4875322. [Epub ahead of print]

Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

Peter McGuire, Tatiana Tarasenko, Emily Warren, Amanda Fuchs, Bharati Singh, Jose Marin, Marten Szibor.

T cell activation, proliferation, and differentiation are fundamentally driven by shifts in cellular metabolism, with mitochondria playing a central role. Cytochrome c oxidase (COX, complex IV) is a key player in this process, as its activity is crucial for apoptosis, mtDNA maintenance, mitochondrial transcription, and mitochondrial respiration (MR), all of which influence T cell fate and function. Despite its known roles, the specific functions of COX required for T cell activity in vivo remain unclear. To isolate the role of MR in T cell function, we reintroduced this capability in COX-deficient T cells using an alternative oxidase (AOX) from Ciona intestinalis. Our findings demonstrate that MR is vital for maintaining metabolic balance during T cell activation by alleviating electron pressure from metabolic reprogramming and preserving redox homeostasis. We further showed that AOX mitigates apoptosis, prevents metabolic disruptions in glycolysis and the tricarboxylic acid cycle, and improves mtDNA maintenance and transcription, indicating that these disturbances are secondary to impaired MR in the absence of COX. Most importantly, the introduction of AOX restored robust effector and memory T cell generation and function in COX-deficient cells. These results highlight the essential role of COX-dependent MR in ensuring cellular health and underscore its pivotal role in T cell proliferation and differentiation.

DOI: https://doi.org/10.21203/rs.3.rs-4875322/v2
Eur J Immunol. 2024 Sep 23. e2451139

Innate immunity champions: The diverse functions of macrophages.

Francesca Biscu, Anissa Zouzaf, Donatella Cicia, Clare Pridans, Gianluca Matteoli.

  Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.

Keywords:  Chronic diseases; Inflammation; Macrophages; Metabolism; Therapies

DOI:  https://doi.org/10.1002/eji.202451139
Sci Immunol. 2024 Sep 20. 9(99): eadp3475

Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.

Darren R Heintzman, Rachael C Sinard, Emilie L Fisher, Xiang Ye, Andrew R Patterson, Joel H Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U Chowdhury, Emily N Arner, Evan S Krystoviak, Frank M Mason, Yasmine T Toudji, KayLee K Steiner, Wasay Khan, Lana M Olson, Angela L Jones, Hanna S Hong, Lindsay Bass, Katherine L Beier, Wentao Deng, Costas A Lyssiotis, Dawn C Newcomb, Alexander G Bick, W Kimryn Rathmell, John T Wilson, Jeffrey C Rathmell.

Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.

DOI: https://doi.org/10.1126/sciimmunol.adp3475
Biomed Pharmacother. 2024 Sep 24. pii: S0753-3322(24)01380-5. [Epub ahead of print]180 117494

Mitochondrial metabolism regulated macrophage phenotype in myocardial infarction.

Youli Kong, Qing Zhang, Shiqi Wang, Ran Li, Chenying Fu, Quan Wei.

  Cardiovascular disease (CVD) remains the leading cause of death worldwide, with myocardial infarction (MI) being the primary contributor to mortality and disability associated with CVD. Reperfusion therapies are widely recognized as effective strategies for treating MI. However, while intended to restore blood flow, the reperfusion processes paradoxically initiate a series of pathophysiological events that worsen myocardial injury, resulting in ischemia-reperfusion (I/R) injury. Therefore, there is a pressing need for new treatment strategies to reduce the size of MI and enhance cardiac function post-infarction. Macrophages are crucial for maintaining homeostasis and mitigating undesirable remodeling following MI. Extensive research has established a strong link between cellular metabolism and macrophage function. In the context of MI, macrophages undergo adaptive metabolic reprogramming to mount an immune response. Moreover, mitochondrial metabolism in macrophages is evident, leading to significant changes in their metabolism. Therefore, we need to delve deeper into summarizing and understanding the relationship and role between mitochondrial metabolism and macrophage phenotype, and summarize existing treatment methods. In this review, we explore the role of mitochondria in shaping the macrophage phenotype and function. Additionally, we summarize current therapeutic strategies aimed at modulating mitochondrial metabolism of macrophages, which may offer new insights treating of MI.

Keywords:  Macrophage phenotype; Mitochondrial metabolism; Mitophagy; Myocardial infarction; Phagocytosis

DOI:  https://doi.org/10.1016/j.biopha.2024.117494
Front Oncol. 2024 ;14 1451650

Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.

Jinkun Xia, Chaoyu Wang, Biao Li.

  Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αβ T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.

Keywords:  fatty acid; hepatocellular carcinoma; metabolic reprogramming; tumor immune microenvironment; γδT cells

DOI:  https://doi.org/10.3389/fonc.2024.1451650
Infect Immun. 2024 Sep 26. e0028424

Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.

Savannah E Sanchez, Travis J Chiarelli, Margaret A Park, Jason A Carlyon.

  Orientia tsutsugamushi a causal agent of scrub typhus, is an obligate intracellular bacterium that, akin to other rickettsiae, is dependent on host cell-derived nutrients for survival and thus pathogenesis. Based on limited experimental evidence and genome-based in silico predictions, O. tsutsugamushi is hypothesized to parasitize host central carbon metabolism (CCM). Here, we (re-)evaluated O. tsutsugamushi dependency on host cell CCM as initiated by glucose and glutamine. Orientia infection had no effect on host glucose and glutamine consumption or lactate accumulation, indicating no change in overall flux through CCM. However, host cell mitochondrial activity and ATP levels were reduced during infection and correspond with lower intracellular glutamine and glutamate pools. To further probe the essentiality of host CCM in O. tsutsugamushi proliferation, we developed a minimal medium for host cell cultivation and paired it with chemical inhibitors to restrict the intermediates and processes related to glucose and glutamine metabolism. These conditions failed to negatively impact O. tsutsugamushi intracellular growth, suggesting the bacterium is adept at scavenging from host CCM. Accordingly, untargeted metabolomics was utilized to evaluate minor changes in host CCM metabolic intermediates across O. tsutsugamushi infection and revealed that pathogen proliferation corresponds with reductions in critical CCM building blocks, including amino acids and TCA cycle intermediates, as well as increases in lipid catabolism. This study directly correlates O. tsutsugamushi proliferation to alterations in host CCM and identifies metabolic intermediates that are likely critical for pathogen fitness.IMPORTANCEObligate intracellular bacterial pathogens have evolved strategies to reside and proliferate within the eukaryotic intracellular environment. At the crux of this parasitism is the balance between host and pathogen metabolic requirements. The physiological basis driving O. tsutsugamushi dependency on its mammalian host remains undefined. By evaluating alterations in host metabolism during O. tsutsugamushi proliferation, we discovered that bacterial growth is independent of the host's nutritional environment but appears dependent on host gluconeogenic substrates, including amino acids. Given that O. tsutsugamushi replication is essential for its virulence, this study provides experimental evidence for the first time in the post-genomic era of metabolic intermediates potentially parasitized by a scrub typhus agent.

Keywords:  Orientia tsutsugamushi; Rickettsiales; amino acid parasitism; central carbon metabolism; intracellular pathogen; nutrient parasitism; obligate intracellular bacterium; rickettsial disease; scrub typhus; untargeted metabolomics

DOI:  https://doi.org/10.1128/iai.00284-24
J Lipid Res. 2024 Sep 19. pii: S0022-2275(24)00150-0. [Epub ahead of print] 100645

Toxoplasma acyl-CoA synthetase TgACS3 is crucial to channel host fatty acids in lipid droplets and for parasite propagation.

Sheena Dass, Serena Shunmugam, Sarah Charital, Samuel Duley, Christophe-Sébastien Arnold, Nicholas J Katris, Pierre Cavaillès, Marie-France Cesbron-Delauw, Yoshiki Yamaryo-Botté, Cyrille Y Botté.

  Apicomplexa comprise important pathogenic parasitic protists that heavily depend on lipid acquisition to survive within their human host cells. Lipid synthesis relies on the incorporation of an essential combination of fatty acids (FAs) either generated by a metabolically adaptable de novo synthesis in the parasite or by scavenging from the host cell. The incorporation of FAs into membrane lipids depends on their obligate metabolic activation by specific enzyme groups, acyl-CoA synthetases (ACSs). Each ACS has its own specificity, so they can fulfill specific metabolic functions. Whilst such functionalities have been well studied in other eukaryotic models, their roles and importance in Apicomplexa is currently very limited, especially for Toxoplasma gondii. Here, we report the identification of 7 putative ACSs encoded by the genome of T. gondii (TgACS), which localize to different sub-cellular compartments of the parasite, suggesting exclusive functions. We show that the perinuclear/cytoplasmic TgACS3 regulates replication and growth of Toxoplasma tachyzoites. Conditional disruption of TgACS3 shows that the enzyme is required for parasite propagation and survival, especially under high host nutrient content. Lipidomic analysis of parasites lacking TgACS3 reveals its role in the activation of host-derived FAs that are used for i) parasite membrane phospholipid and ii) storage triacylglycerol (TAG) syntheses, allowing proper membrane biogenesis of parasite progenies. Altogether, our results reveal the role of TgACS3 as the bulk FA activator for membrane biogenesis allowing intracellular division and survival in T. gondii tachyzoites, further pointing at the importance of ACS and FA metabolism for the parasite.

Keywords:  Acyl-CoA synthetase; Apicomplexa; Lipid metabolism; Lipidomic; Toxoplasma gondii; fatty acid activation; host-parasite metabolic interactions; lipid-fatty acid fluxes; membrane biogenesis

DOI:  https://doi.org/10.1016/j.jlr.2024.100645
Nat Immunol. 2024 Oct;25(10): 1884-1899

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.

DOI: https://doi.org/10.1038/s41590-024-01963-1
Adv Sci (Weinh). 2024 Sep 26. e2403629

Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape.

Xinyi Zhou, Zhiqiang Chen, Yijiang Yu, Mengjiao Li, Yu Cao, Edward V Prochownik, Youjun Li.

  Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti-tumor immunity mediated by CD8+ T cells. In HCCs, depletion of PMVK is required to facilitate CD8+ T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ-aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl-CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4-acetaminobutyric acid (4-Ac-GABA), which is released into the TME. There, 4-Ac-GABA activates the GABAA receptor (GABAAR) on CD8+ T cells, which inhibits AKT1 signaling. This in turn suppresses CD8+ T cell activation, intratumoral infiltration, and the anti-tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti-PD-1 immune checkpoint therapy. These findings reveal non-canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8+ T cell inhibitor 4-Ac-GABA. Blocking 4-Ac-GABA signaling in CD8+ T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.

Keywords:  4‐Acetaminobutyric acids; GABAA receptors; PMVK; immune escapes; tumor metabolisms

DOI:  https://doi.org/10.1002/advs.202403629
MedComm (2020). 2024 Oct;5(10): e747

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells.

Panpan Jiang, Siyu Zhao, Xiaoyu Li, Shiyan Hu, Shuhan Chen, Yinming Liang, Lichen Zhang, Liaoxun Lu, Guofeng Fang, Lu Yang, Yanmei Huang, Heather Miller, Fei Guan, Jiahui Lei, Chaohong Liu.

  Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.

Keywords:  DOCK8; T cell; differentiation; glycolytic

DOI:  https://doi.org/10.1002/mco2.747
bioRxiv. 2024 Sep 13. pii: 2024.08.19.608538. [Epub ahead of print]

Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.

Sarah Staudt, Fabian Nikolka, Markus Perl, Julia Franz, Noemie Leblay, Xiaoli-Kat Yuan, Linda Warmuth, Matthias A Fantes, Aiste Skorpskaite, Teng Fei, Maria Bromberg, Patxi San Martin-Uriz, Juan Roberto Rodriguez-Madoz, Kai Ziegler-Martin, Nazdar Adil-Gholam, Pascal Benz, Phuc Tran Huu, Christoph Stein-Thoeringer, Michael Schmitt, Karin Kleigrewe, Fabian Freitag, Zeno Riester, Justus Weber, Kira Mangold, Hermann Einsele, Felipe Prosper, Wilfried Ellmeier, Dirk Busch, Alexander Visekruna, John Slingerland, Roni Shouval, Karsten Hiller, Marcel van den Brink, Patrick Pausch, Paola Neri, Michael Hudecek, Hendrik Poeck, Maik Luu.

Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.

DOI: https://doi.org/10.1101/2024.08.19.608538
Nature. 2024 Sep 25.

Phages reconstitute NAD+ to counter bacterial immunity.

Ilya Osterman, Hadar Samra, Francois Rousset, Elena Loseva, Maxim Itkin, Sergey Malitsky, Erez Yirmiya, Adi Millman, Rotem Sorek.

Bacteria defend against phage infection through a variety of antiphage defence systems1. Many defence systems were recently shown to deplete cellular nicotinamide adenine dinucleotide (NAD+) in response to infection, by cleaving NAD+ into ADP-ribose (ADPR) and nicotinamide2-7. It was demonstrated that NAD+ depletion during infection deprives the phage of this essential molecule and impedes phage replication. Here we show that a substantial fraction of phages possess enzymatic pathways allowing reconstitution of NAD+ from its degradation products in infected cells. We describe NAD+ reconstitution pathway 1 (NARP1), a two-step pathway in which one enzyme phosphorylates ADPR to generate ADPR pyrophosphate (ADPR-PP), and the second enzyme conjugates ADPR-PP and nicotinamide to generate NAD+. Phages encoding NARP1 can overcome a diverse set of defence systems, including Thoeris, DSR1, DSR2, SIR2-HerA and SEFIR, all of which deplete NAD+ as part of their defensive mechanism. Phylogenetic analyses show that NARP1 is primarily encoded on phage genomes, suggesting a phage-specific function in countering bacterial defences. A second pathway, NARP2, allows phages to overcome bacterial defences by building NAD+ using metabolites different from ADPR-PP. Our findings reveal a unique immune evasion strategy in which viruses rebuild molecules depleted by defence systems, thus overcoming host immunity.

DOI: https://doi.org/10.1038/s41586-024-07986-w
JCI Insight. 2024 Sep 26. pii: e181329. [Epub ahead of print]

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Ariane R Pessentheiner, Nathanael J Spann, Chloe A Autran, Tae Gyu Oh, Kaare V Grunddal, Joanna Kc Coker, Chelsea D Painter, Bastian Ramms, Austin Wt Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno Pj de Winther, Hal M Hoffman, Martin Philpott, Adam P Cribbs, Udo Oppermann, Nathan E Lewis, Joseph L Witztum, Ruth Yu, Annette R Atkins, Michael Downes, Ron M Evans, Christopher K Glass, Lars Bode, Philip Lsm Gordts.

  Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Keywords:  Atherosclerosis; Cell biology; Epigenetics; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.181329