A Tc1‐ and Th1‐T‐lymphocyte‐rich tumor microenvironment is a hallmark of MSI colorectal cancer

The Journal of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Abstract Microsatellite instability is a strong predictor of response to immune checkpoint therapy and patient outcome in colorectal cancer. Although enrichment distinct T‐cell subpopulations has been determined impact the outcome, little known about underlying changes composition tumor microenvironment. To assess density, composition, degree functional marker expression, spatial interplay subpopulations, 79 microsatellite instable (MSI) 1,045 stable (MSS) cancers were analyzed. A tissue microarray large sections stained with 19 antibodies directed against T cells, antigen‐presenting markers, structural proteins using our BLEACH&STAIN multiplex‐fluorescence immunohistochemistry approach. deep learning‐based framework comprising >20 different convolutional neuronal networks was developed for image analysis. The Type 1 (T‐bet + ), 2 (GATA3 17 (RORγT NKT‐like (CD56 regulatory (FOXP3 follicular (BCL6 cytotoxic (CD3 CD8 ) or helper CD4 cells showed marked differences between MSI MSS patients. For instance, fraction Tc1 Th1 significantly higher ( p < 0.001 each), while Tregs, Th2, Th17 lower 0.05) compared TIM3, CTLA‐4, PD‐1 expression on most patients 0.05 each). Spatial analysis revealed increased interactions Th1, Tc1, dendritic patients, strongest found Th17, cells. additional 12 divergent at invasive margin. In summary, this study identified accompanied by paucity T‐cell, Th2 along interaction profile, as hallmark cancers. © 2025 Author(s). Journal Pathology published John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.

Language: Английский

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A new era in melanoma immunotherapy: focus on DCs metabolic reprogramming

Cancer Cell International, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 15, 2025

Melanoma, being one of the most dangerous forms skin cancer, is characterized by its aggressive and metastatic nature, with potential to develop resistance various treatments. This makes disease challenging treat, emphasizing need for new treatment strategies. Within tumor microenvironment (TME), melanoma cells exploit metabolic shifts, particularly glycolysis, create an immunosuppressive TME that prevents dendritic (DCs) from functioning properly. Essential alterations such as lactate lipid accumulation, lack tryptophan disrupt DC maturation, antigen presentation, T cell activation. In recent years, immunotherapy has increasingly focused on reprogramming metabolism DCs. review paper aims provide insights into suppression melanoma-associated DCs, allowing design therapeutic strategies based interventions promote or restore function. contribution reviews DCs a approach immunotherapy.

Language: Английский

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Cancer vaccines: from an immunology perspective

Immunotherapy Advances, Journal Year: 2023, Volume and Issue: 4(1)

Published: Dec. 21, 2023

Abstract The concept of a therapeutic cancer vaccine to activate anti-tumour immunity pre-dates innovations in checkpoint blockade immunotherapies. However, vaccination strategies have yet show the hoped-for successes patients, and unanswered questions regarding underlying immunological mechanisms behind vaccines hampered translation clinical practice. Recent advances our understanding potential tumour mutational burden neo-antigen-reactive T cells for response immunotherapy re-ignited enthusiasm strategies, coupled with development novel mRNA-based following prevention COVID-19. Here we summarise current developments discuss how comprehension cellular interplay immunotherapy-responsive tumours may inform better design vaccines, focus on role dendritic as orchestrators immunity. increasing number trials research being funnelled into has demonstrated ‘proof-of-principle’, supporting hypothesis that an immuno-oncology agent. For efficacious safe be developed, underpinning is paramount.

Language: Английский

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Targeting metabolic pathways to counter cancer immunotherapy resistance

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(7), P. 486 - 494

Published: June 13, 2024

Language: Английский

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Progress in Lactate Metabolism and Its Regulation via Small Molecule Drugs

Molecules, Journal Year: 2024, Volume and Issue: 29(23), P. 5656 - 5656

Published: Nov. 29, 2024

Lactate, once viewed as a byproduct of glycolysis and metabolic “waste”, is now recognized an energy-providing substrate signaling molecule that modulates cellular functions under pathological conditions. The discovery histone lactylation in 2019 marked paradigm shift, with subsequent studies revealing lactate can undergo both non-histone proteins, implicating it the pathogenesis various diseases, including cancer, liver fibrosis, sepsis, ischemic stroke, acute kidney injury. Aberrant metabolism associated disease onset, its levels predict outcomes. Targeting production, transport, may offer therapeutic potential for multiple yet systematic summary small molecules modulating diseases lacking. This review outlines sources clearance lactate, well roles myocardial infarction, injury, summarizes effects on regulation. It aims to provide reference direction future research.

Language: Английский

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Respiratory Virus-Induced PARP1 Alters DC Metabolism and Antiviral Immunity Inducing Pulmonary Immunopathology

Viruses, Journal Year: 2024, Volume and Issue: 16(6), P. 910 - 910

Published: June 4, 2024

Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation DC. Real-time analysis demonstrated glycolysis PARP1-/- after infection, confirming role for regulating Our show enzymatic inhibition or genomic ablation resulted ifnb1, il12, il27 which, together, promote more appropriate anti-viral environment. mice PARP1-inhibitor-treated were protected against immunopathology including airway inflammation, Th2 cytokine production, mucus hypersecretion. However, delayed treatment with inhibitor provided only partial protection, suggesting is most important during earlier innate immune stage infection.

Language: Английский

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Rps3 Attenuates Gastric Precancerous Lesions by Promoting Dendritic Cells Maturation via AKT/β-Catenin Pathway

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 22, 2024

This study aimed to investigate the dysregulated proteins and underlying mechanisms of gastric precancerous lesions. Proteomic phosphoproteomic methods were used characterize proteome phosphoproteome profiles

Language: Английский

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Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(10)

Published: Oct. 18, 2024

Abstract Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well controlling polarization T cells. Obesity, chronic inflammatory condition, characterized by immune various tissues. We hypothesized SIRT1 might influence phenotype functions DCs through Ido1 pathway, ultimately leading to towards pro-inflammatory obesity. In our study, we observed activity was reduced bone marrow-derived (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) increased extracellular acidification rates (ECAR), along with enhanced expression II MHC, CD86, CD40, secretion IL-12p40, while production TGF-β reduced. The kynurenine pathway decreased animals, particularly under inhibition. positively regulated PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed mice had differentially open chromatin regions compared those lean mice, accessibility at Sirt1 genomic locus WT mice. Gene Ontology (GO) enrichment indicated animals disrupted metabolic pathways, including related GTPase insulin response. Differential showed levels Pparg which challenged confirmed using conditional knockout (SIRT1∆). This study highlights controls metabolism modulation significant implications for obesity-related inflammation.

Language: Английский

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Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

We discuss the recent advances in nanomaterial design strategies for immunometabolic modulatory platforms and their applications targeting cancer-immunity cycle to enhance therapeutic outcomes.

Language: Английский

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Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 20, 2024

Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well controlling polarization T cells. Obesity, chronic inflammatory condition, characterized by immune various tissues. We hypothesized SIRT1 might influence phenotype functions DCs through Ido1 pathway, ultimately leading to towards proinflammatory obesity. In our study, we observed activity was reduced bone marrow-derived (BMDCs) from obese animals. These BMDCs exhibited diminished oxidative phosphorylation (OXPHOS) increased extracellular acidification rates (ECAR), along with enhanced expression II MHC, CD86, CD40, elevated secretion IL-12p40, while production TGF-β reduced. The kynurenine pathway decreased animals, particularly under inhibition. positively regulated PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed mice had differentially open chromatin regions compared those lean mice, accessibility at Sirt1 genomic locus WT mice. Gene Ontology (GO) enrichment indicated animals disrupted metabolic pathways, including related GTPase insulin response. Differential showed levels Pparg This study highlights controls metabolism modulation Ido1, significant implications for obesity-related inflammation.

Language: Английский

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