Asparagine availability controls B cell homeostasis DOI Creative Commons
Yavuz F. Yazicioglu,

Eros Marin,

Hana F. Andrew

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 5, 2023

Abstract Germinal centre (GC) B cells proliferate at some of the highest rates any mammalian cell, yet metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling GC cells, found that metabolism non-essential amino acid asparagine (Asn) was highly upregulated. Asn conditionally essential to its synthetic enzyme, synthetase (ASNS) upregulated following their activation, particularly more markedly in absence Asn, through stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted cell survival proliferation low conditions were strongly impaired, removal environmental by asparaginase or dietary restriction compromised reaction, impairing affinity maturation humoral influenza infection. Using stable isotope tracing single RNA sequencing, we adaptation requires ASNS, oxidative phosphorylation, mitochondrial homeostasis, synthesis nucleotides sensitive deprivation. Altogether, reveal acts as a key regulator function homeostasis. The one sentence summary Asparagine critical function, maintaining germinal reaction.

Language: Английский

Advances in single-cell RNA sequencing and its applications in cancer research DOI Creative Commons
Dezhi Huang,

Naya Ma,

Xinlei Li

et al.

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

Published: Aug. 24, 2023

Abstract Cancers are a group of heterogeneous diseases characterized by the acquisition functional capabilities during transition from normal to neoplastic state. Powerful experimental and computational tools can be applied elucidate mechanisms occurrence, progression, metastasis, drug resistance; however, challenges remain. Bulk RNA sequencing techniques only reflect average gene expression in sample, making it difficult understand tumor heterogeneity microenvironment. The emergence development single-cell (scRNA-seq) technologies have provided opportunities subtle changes biology identifying distinct cell subpopulations, dissecting microenvironment, characterizing cellular genomic mutations. Recently, scRNA-seq technology has been increasingly used cancer studies explore which increased understanding tumorigenesis evolution. This review summarizes basic processes their increasing applications research clinical practice.

Language: Английский

Citations

86
Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy DOI Creative Commons
Jeremy Baldwin, Christoph Heuser, Tanmoy Saha

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(23), P. 6614 - 6630.e21

Published: Sept. 13, 2024

Language: Английский

Citations

39
Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations DOI Creative Commons

Hsuan-Chia Chang,

Chung‐Ying Tsai,

Cheng-Lung Hsu

et al.

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The L-asparaginase notably immune-checkpoint blockade therapy in by strengthening CD8+T fitness. Our study shows this combination is a promising avenue for clinical application and provides further mechanistic insight into how restriction rewires metabolism.

Language: Английский

Citations

2
Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors DOI Creative Commons
Cody N. Heiser, Alan J. Simmons,

Frank Revetta

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(25), P. 5620 - 5637.e16

Published: Dec. 1, 2023

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data 31 human colorectal specimens enabled phylogeographic mapping tumor evolution that revealed individualized trajectories accompanying microenvironmental clonal alterations. Phylogeographic ordered events, classified tumors by their evolutionary dynamics, placed regions along global pseudotemporal encompassing the chromosomal instability (CIN+) hypermutated (HM) pathways. Integrated single-cell transcriptomic recurring epithelial programs infiltrating immune states pseudotime. We discovered an exclusion signature (IEX), consisting extracellular matrix regulators DDR1, TGFBI, PAK4, DPEP1, charts with CIN+ progression, is associated reduced cytotoxic cell infiltration, shows prognostic value in independent cohorts. This atlas provides insights into tumor-microenvironment co-evolution, serving as a resource for stratification targeted treatments.

Language: Английский

Citations

40
ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition DOI Creative Commons

Ziqi Zou,

Qian Cheng,

Jiajie Zhou

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 113995 - 113995

Published: March 23, 2024

The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how levels fluctuate TME to shape fates. Here, we find that 20-μM low condition, representing found plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated cells. In vivo mouse models and human single-cell RNA-sequencing datasets reveal positive correlations between condition intratumoral Treg accumulation. Mechanistically, arginine-activated cells engage transcriptional reprogramming, using ATF4-SLC7A11-GSH axis, preserve their suppressive function. These findings improve our understanding role biology potential applications for immunotherapy strategies.

Language: Английский

Citations

17
Exploiting pancreatic cancer metabolism: challenges and opportunities DOI Creative Commons
Maria Chiara De Santis, Bruno Bockorny, Emilio Hirsch

et al.

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(6), P. 592 - 604

Published: April 10, 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its challenging diagnosis and limited treatment options. The focus on metabolic reprogramming as key factor in tumor initiation, progression, therapy resistance has gained prominence. In this review we the impact changes interplay among stromal, immune, cells, glutamine branched-chain amino acids (BCAAs) emerge pivotal players modulating immune cell functions growth. We also discuss ongoing clinical trials that explore modulation PDAC, targeting mitochondrial metabolism, asparagine addiction, autophagy inhibition. Overcoming challenges understanding nutrient effects immune-stromal-tumor interactions holds promise innovative therapeutic strategies.

Language: Английский

Citations

17
The High-Affinity IL-2 Receptor Affects White Matter Damage after Cerebral Ischemia by Regulating CD8 + T Lymphocyte Differentiation DOI

Yuqian Li,

Qian Jiang,

Xiaokun Geng

et al.

Journal of Neuroimmune Pharmacology, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 16, 2025

Language: Английский

Citations

1
Immunotherapy: an emerging modality to checkmate brain metastasis DOI Creative Commons

Aatiya Ahmad,

Parvez Κhan, Asad Rehman

et al.

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

Published: July 15, 2023

Abstract The diagnosis of brain metastasis (BrM) has historically been a dooming that is nothing less than death sentence, with few treatment options for palliation or prolonging life. Among the available, radiotherapy (RT) and surgical resection have backbone therapy. Within past couple years, immunotherapy (IT), alone in combination traditional treatments, emerged as reckoning force to combat spread BrM shrink tumor burden. This review compiles recent reports describing potential role IT various cancers. It also examines impact microenvironment on regulating cancer can play mitigating spread. Lastly, this focuses future new clinical trials pushing boundaries BrM.

Language: Английский

Citations

23
Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity DOI Creative Commons
Lihaoyun Huang, Haitao Li, Cangang Zhang

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

Abstract As single‐cell RNA sequencing enables the detailed clustering of T‐cell subpopulations and facilitates analysis metabolic states metabolite dynamics, it has gained prominence as preferred tool for understanding heterogeneous cellular metabolism. Furthermore, synergistic or inhibitory effects various pathways within T cells in tumour microenvironment are coordinated, increased activity specific generally corresponds to functional activity, leading diverse behaviours related immune cells, which shows potential tumour‐specific induce persistent responses. A holistic how heterogeneity governs function subsets is key obtaining field‐level insights into immunometabolism. Therefore, exploring mechanisms underlying interplay between metabolism functions will pave way precise immunotherapy approaches future, empower us explore new methods combating tumours with enhanced efficacy.

Language: Английский

Citations

6
Age- and diet-instructed metabolic rewiring of the tumor–immune microenvironment DOI
Ana Belén Plata-Gómez, Ping‐Chih Ho

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(6)

Published: April 11, 2025

The tumor–immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of cells fosters an immunosuppressive state by intervening metabolic reprogramming infiltrating immune cells. Aging diet significantly impact TIME, contributing to cancer progression evasion. With aging, cell function declines, leading proinflammatory alterations such increased oxidative stress mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat high-sugar diets, promote shifts, creating permissive TIME fostering tumor-supportive phenotypes while impairing tumoricidal activity In contrast, restrictions have been shown restore modulating metabolism enhancing responses. Here, we discuss intricate interplay between diet, shaping with particular focus on T cells, highlight therapeutic strategies targeting these pathways empower

Language: Английский

Citations

0