High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis

Cancer Immunology Research, Journal Year: 2023, Volume and Issue: 11(4), P. 405 - 420

Published: Jan. 18, 2023

Abstract Patients with colorectal liver metastasis (CLM) present heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated distinct populations opposite relevance. The invasive margin CLM was enriched in pro-inflammatory monocyte-derived (MoMϕ) expressing monocytic marker SERPINB2, more differentiated population, tumor-associated (TAM), glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were pathways matrix degradation, angiogenesis, lipid metabolism found closer tumor margin, confirmed by spatial transcriptomics on specimens. In cohort patients, high infiltration cells independently longer disease-free survival (DFS; P = 0.033), density correlated shorter DFS (P 0.012) overall 0.002). Cell–cell interaction defined opposing roles for TAMs, suggesting that are discrete may be exploited further translation immune-based stratification tool. This study provides evidence how multi-omics approaches can identify nonredundant, clinically relevant patient tools GPNMB has been shown set immunosuppressive mode. Our dimensional analyses provide negative indicator potential player protumor function populations.

Language: Английский

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Interplay between metabolic reprogramming and post-translational modifications: from glycolysis to lactylation

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 29, 2023

Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming its byproducts have complex impact on cellular activities. In quiescent T cells, oxidative phosphorylation (OXPHOS) is primary pathway for survival. However, upon antigen activation, cells undergo rapid metabolic reprogramming, characterized by an elevation both glycolysis OXPHOS. While pathways are induced, balance predominantly shifts towards glycolysis, enabling to rapidly proliferate enhance their functionality, representing most distinctive signature during activation. processes generate various small molecules resulting from enzyme-catalyzed reactions, which also modulate protein exert regulatory control. Notably, recent studies revealed direct modification histones, known as lactylation, lactate derived glycolysis. This lactylation process influences gene transcription adds novel variable regulation expression. Protein has been identified essential mechanism exerts diverse functions, contributing crucial biological such uterine remodeling, tumor proliferation, neural system regulation, regulation. review focuses explores interplay between immune system, highlights function, elucidates intersection epigenetics.

Language: Английский

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Immunosurveillance encounters cancer metabolism

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(2), P. 471 - 488

Published: Jan. 12, 2024

Abstract Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, redox demands. Similarly, processes in immune support host immunity against cancer determine differentiation fate of leukocytes. Thus, deregulation imbalance within the tumor microenvironment have been reported drive evasion compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor could modulate heterogeneity, aggressiveness, reprogramming, suggesting immunosurveillance can instruct progression multiple dimensions. This review summarizes our current understanding how crosstalk tumors affects immunogenicity promotes progression. Furthermore, we explain defects cascade contribute developing dysfunctional responses cancers discuss contribution these as a feedback mechanism. Finally, highlight ongoing clinical trials new strategies targeting cellular metabolism cancer.

Language: Английский

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Traditional Chinese medicine in regulating macrophage polarization in immune response of inflammatory diseases

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 325, P. 117838 - 117838

Published: Feb. 3, 2024

Language: Английский

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Metabolic Reprogramming of Tumor-Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancers

Cancer Immunology Research, Journal Year: 2024, Volume and Issue: 12(7), P. 854 - 875

Published: April 26, 2024

Abstract Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent growth inhibition urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism induced TNF, proinflammatory, mTORC1 signaling intratumoral TAM clusters. TAMs also exhibited increased cell phagocytosis diminished proangiogenic capacities. In vivo of consumption resulted glycolysis, a broken tricarboxylic acid (TCA) cycle, purine disruption. Although effect on T cells was moderate, JHU083 promoted stem cell–like phenotype CD8+ decreased abundance regulatory cells. Finally, caused global shutdown glutamine-utilizing metabolic pathways cells, leading to reduced HIF-1α, c-MYC phosphorylation, induction apoptosis, all key features. Altogether, our findings demonstrate that targeting with led suppressed as well reprogramming immunosuppressive within prostate bladder immune responses. can offer an effective therapeutic benefit for types are enriched TAMs.

Language: Английский

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