Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: June 5, 2023

Abstract Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the response. Regarding metabolic reprogramming in tumor microenvironment, dysregulation of amino acid consumption is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered metabolism tightly linked outgrowth, metastasis, therapeutic resistance through governing fate various cells. During these processes, concentration free acids, their membrane bound transporters, key enzymes, sensors such as mTOR GCN2 play critical roles controlling cell differentiation function. As such, anti-cancer responses could be enhanced by supplement specific essential or targeting enzymes sensors, thereby developing novel adjuvant modalities. To further dissect regulation immunity, this review summarizes regulatory mechanisms effects on phenotypes functions tumor-infiltrating propose approaches exploited rewire enhance cancer immunotherapy.

Language: Английский

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Immune regulation through tryptophan metabolism

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(7), P. 1371 - 1379

Published: July 3, 2023

Amino acids are fundamental units of molecular components that essential for sustaining life; however, their metabolism is closely interconnected to the control systems cell function. Tryptophan (Trp) an amino acid catabolized by complex metabolic pathways. Several resulting Trp metabolites bioactive and play central roles in physiology pathophysiology. Additionally, various physiological functions mutually regulated gut microbiota intestine coordinately maintain intestinal homeostasis symbiosis under steady state conditions during immune response pathogens xenotoxins. Cancer inflammatory diseases associated with dysbiosis- host-related aberrant inactivation aryl hydrocarbon receptor (AHR), which a several metabolites. In this review, we focus on mechanisms through converges AHR activation modulation function restoration tissue how these processes can be targeted using therapeutic approaches cancer autoimmune diseases.

Language: Английский

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Exploiting innate immunity for cancer immunotherapy

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Nov. 27, 2023

Abstract Immunotherapies have revolutionized the treatment paradigms of various types cancers. However, most these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although agents already achieved great success, only a tiny percentage patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined multiple components in tumor microenvironment beyond immunity. Cells innate arm system, such as macrophages, dendritic cells, myeloid-derived suppressor neutrophils, natural killer unconventional also participate cancer evasion surveillance. Considering that cornerstone antitumor response, utilizing immunity provides potential therapeutic options for control. Up to now, exploiting agonists stimulator interferon genes, CAR-macrophage -natural therapies, metabolic regulators, novel exhibited potent activities preclinical clinical studies. Here, we summarize latest insights into roles cells discuss advances arm-targeted strategies.

Language: Английский

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Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(10), P. 1145 - 1160.e9

Published: Sept. 22, 2022

Language: Английский

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Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Immunity, Journal Year: 2022, Volume and Issue: 55(6), P. 1032 - 1050.e14

Published: June 1, 2022

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role different subsets remains unclear. At homeostasis, only mature CCR7+ expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation IDO1-dependent tolerogenic activity isolated immature cDC1, not cDC2. However, human mouse cDC2 could induce acquire function when co-cultured with through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation vivo exacerbated disease experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized communication which IDO1-expressing extend their immunoregulatory capacity subset production metabolite axis represents potential therapeutic target treating demyelinating diseases.

Language: Английский

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Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 13, 2024

Abstract Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment the intestinal tract remains obscure. Here, we demonstrate that understudied murine commensal bacterium, Dubosiella newyorkensis , and its human homologue Clostridium innocuum have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated germ-free mouse models. We identify important for D. rebalancing Treg/Th17 responses ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate L-Lysine (Lys). further show Lys induces immune tolerance ability of dendritic cells (DCs) enhancing Trp catabolism towards kynurenine (Kyn) pathway through activation metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies previously unrecognized communication which Lys-producing exert immunoregulatory capacity establish Treg-mediated immunosuppressive activating AhR-IDO1-Kyn circuitry DCs. circuit represents potential therapeutic target treatment inflammatory bowel diseases.

Language: Английский

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Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression

Science Advances, Journal Year: 2023, Volume and Issue: 9(4)

Published: Jan. 27, 2023

Cervical squamous cell carcinoma (CESC) is a prototypical human cancer with well-characterized pathological stages of initiation and progression. However, high-resolution knowledge the transcriptional programs underlying each stage CESC lacking, important questions remain. We performed single-cell RNA sequencing 76,911 individual cells from 13 samples cervical tissues at various malignancy, illuminating tumorigenic trajectory epithelial revealing key factors involved in In addition, we found significant correlations between abundance specific myeloid, lymphoid, endothelial populations progression CESC, which were also associated patients' prognosis. Last, demonstrated tumor-promoting function matrix cancer-associated fibroblasts via NRG1-ERBB3 pathway CESC. This study provides valuable resource deeper insights into progression, helpful refining diagnosis for design optimal treatment strategies.

Language: Английский

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Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(2)

Published: Feb. 1, 2023

Abstract Background Dendritic cells (DCs) mediate divergent immune effects by activating T or negatively regulating the response to promote tolerance. They perform specific functions determined their tissue distribution and maturation state. Traditionally, immature semimature DCs were described have immunosuppressive effects, leading Nonetheless, recent research has demonstrated that mature can also suppress under certain circumstances. Main body Mature enriched in immunoregulatory molecules (mregDCs) emerged as a regulatory module across species tumour types. Indeed, distinct roles of mregDCs immunotherapy sparked interest researchers field single‐cell omics. In particular, these found be associated with positive favourable prognosis. Conclusion Here, we provide general overview latest most notable advances findings regarding basic features complex nonmalignant diseases microenvironment. We emphasise important clinical implications tumours.

Language: Английский

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Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(733)

Published: Feb. 7, 2024

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there limited knowledge of the molecular and spatial characteristics nonneuronal cells, well interactions between cell types in ischemic brain. Here, we used transcriptomics to study hemisphere mice stroke sequenced transcriptomes 19,777 spots, allowing us both visualize transcriptional landscape within tissue identify gene expression profiles linked specific histologic entities. Cell identified by single-cell RNA sequencing confirmed enriched annotation ischemia-associated peri-infarct area hemisphere. Analysis ligand-receptor communication revealed galectin-9 cell-surface glycoprotein CD44 (LGALS9-CD44) critical signaling pathway injury microglia macrophages main source galectins stroke. Extracellular vesicle–mediated Lgals9 delivery improved long-term functional recovery photothrombotic mice. Knockdown Cd44 partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation remyelination. In summary, our provides detailed cellular characterization peri-infact murine model potential treatment target that warrants further investigation.

Language: Английский

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The significant role of amino acid metabolic reprogramming in cancer

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 29, 2024

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming amino acids cells is intricately linked to protein synthesis, nucleotide modulation signaling pathways, regulation cell metabolism, maintenance oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation also impacts microenvironment immunity. can act as molecules that modulate immune function tolerance within reshaping anti-tumor response promoting evasion by cells. Moreover, influence behavior stromal cells, such cancer-associated fibroblasts, regulate ECM remodeling promote angiogenesis, thereby facilitating growth metastasis. Understanding intricate interplay between crucial significance. Expanding our knowledge multifaceted roles holds significant promise for development more effective therapies aimed at disrupting dependencies modulating enhance responses inhibit

Language: Английский

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