Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity

Gut, Journal Year: 2023, Volume and Issue: 72(12), P. 2307 - 2320

Published: July 28, 2023

Objective Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role + TAMs regulating immune escape tumour cells and develop novel therapeutic strategies targeting enhance efficacy checkpoint inhibitor (ICI) colorectal cancer. Design inhibitory effect blockade alone or combined with ICI treatment on growth was assessed using murine subcutaneous orthotopic transplanted models. microenvironment flow cytometry mass cytometry. RNA sequencing western blot analysis were used further explore molecular mechanism which promoted M2 polarisation. Results different types tumours, associated adverse clinical outcome patients In vivo inhibition anti-MS4A4A monoclonal antibody both curb improve therapy. reshaped microenvironment, resulting reducing infiltration M2-TAMs exhausted T cells, increasing effector CD8 Anti-MS4A4A plus anti-programmed cell death 1 (PD-1) therapy remained effective large, treatment-resistant could induce complete regression when radiotherapy. Mechanistically, polarisation activating PI3K/AKT pathway JAK/STAT6 pathway. Conclusion Targeting represent a new anticancer immunotherapy.

Language: Английский

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Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies

Trends in Immunology, Journal Year: 2023, Volume and Issue: 44(12), P. 971 - 985

Published: Nov. 22, 2023

Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting macrophages has historically focused on inhibiting their recruitment or reprogramming phenotype from protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing (scRNA-seq) spatial transcriptomics improved our understanding ontogeny, phenotype, functional plasticity macrophages. Overlaying wealth current information regarding macrophage molecular subtypes functions also identified novel therapeutic vulnerabilities might drive better control tumor-associated (TAMs). Here, we discuss profiling provide update macrophage-targeted therapies in development.

Language: Английский

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Mechanisms of metastatic colorectal cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(9), P. 609 - 625

Published: May 28, 2024

Language: Английский

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Novel tumor-associated macrophage populations and subpopulations by single cell RNA sequencing

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 29, 2024

Tumor-associated macrophages (TAMs) are present in almost all solid tumor tissues. 16They play critical roles immune regulation, angiogenesis, stem cell activation, invasion and metastasis, resistance to therapy. However, it is unclear how TAMs perform these functions. With the application of single-cell RNA sequencing (scRNA-seq), has become possible identify TAM subpopulations associated with distinct In this review, we discuss four novel tumors based on core gene signatures by scRNA-seq, including FCN1 + , SPP1 C1Q CCL18 TAMs. Functional enrichment expression scRNA-seq data from different tissues found that may induce inflammation; potentially involved cancer whereas participate regulation suppression; And cells terminal immunosuppressive not only have a stronger function but also enhance metastasis. can be further divided into populations Meanwhile, will emerging evidence highlighting separating macrophage there exist potential disconnects between types identified their actual function.

Language: Английский

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IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(3), P. 512 - 524

Published: Feb. 14, 2024

Abstract Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels unclear. Here, we found tumor-associated macrophages be the main source of mouse human microenvironments. Among IL-23-sensing cells, identified subset tumor-infiltrating regulatory T (T reg ) display highly suppressive phenotype across tumors. The use three solid combination genetic ablation Il23r revealed they are responsible for tumor-promoting effect IL-23. Mechanistically, sensing represents crucial signal driving maintenance stabilization effector involving transcription factor Foxp3. Our data support targeting IL-23/IL-23R axis may represent means eliciting antitumor immunity.

Language: Английский

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Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(5), P. 766 - 785

Published: Feb. 6, 2024

Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab 5-FU/platinum GEA. Using serial biopsy primary tumor at baseline, after one cycle 5-FU/platinum, addition pembrolizumab, transcriptionally profiled 358,067 single cells identify evolving multicellular microenvironment (TME) networks. Chemotherapy induced early on-treatment hubs with tumor-reactive T-cell M1-like macrophage interactions slow progressors. Faster progression featured increased MUC5A MSLN containing treatment resistance programs M2-like macrophages immunosuppressive stromal interactions. After observed CD8 infiltration development an immunity hub involving CXCL13 program epithelial interferon-stimulated gene programs. Strategies drive increases antitumor immune formation could expand portion patients benefiting from anti-PD-1 approaches.

Language: Английский

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Complement C3 of tumor-derived extracellular vesicles promotes metastasis of RCC via recruitment of immunosuppressive myeloid cells

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(4)

Published: Jan. 23, 2025

Heterogeneous roles of complement C3 have been implicated in tumor metastasis and are highly context dependent. However, the underlying mechanisms linking to remain elusive renal cell carcinoma (RCC). Here, we demonstrate that RCC cell-derived extracellular vesicles (EVs) contributes via polarizing tumor-associated macrophages (TAMs) into immunosuppressive phenotype recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, EV induces secretion CCL2 CXCL1 by lung subsequently enhances TAM polarization PMN-MDSC recruitment. Notably, targeting CCL2/CCR2 or CXCL1/CXCR2 axis with inhibitors RS504393 Navarixin, respectively, effectively suppresses induced RCC-derived a mouse model. Clinically, patients high expression poor prognosis. Collectively, our findings reveal tumor-derived an microenvironment TAMs, thus promoting metastasis.

Language: Английский

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Statistical identification of cell type-specific spatially variable genes in spatial transcriptomics

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 26, 2025

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)—a subset of exhibiting distinct expression patterns within specific types. Celina utilizes varying coefficient model to accurately capture each gene's pattern relation the distribution types across tissue locations, ensuring effective type I error control and high power. proves powerful compared existing methods single-cell resolution stands as only solution spot-resolution transcriptomics. Applied five real datasets, uncovers ct-SVGs associated with tumor progression patient survival lung cancer, identifies metagenes unique linked proliferation immune response kidney detects preferentially expressed near amyloid-β plaques an Alzheimer's model. The authors develop detect (ct-SVGs) These exhibit types, offering insights into transcriptomic mechanism underlying cellular heterogeneity.

Language: Английский

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C3‐dependent effector functions of complement

Immunological Reviews, Journal Year: 2022, Volume and Issue: 313(1), P. 120 - 138

Published: Oct. 22, 2022

Summary C3 is the central effector molecule of complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce forms (native C3, [H 2 O], intracellular C3), fragments C3a, C3b, iC3b, C3dg/C3d, expression sites. To highlight important role that plays in human biological processes, we give an overview diseases linked to deficiency uncontrolled activation. Next, present a structural description activation generated by regulation. proceed describing C3a interaction with anaphylatoxin receptor, followed interactions opsonins (C3b, C3dg/C3d) receptors, divided into two groups: receptors bearing regulatory without activity. outline molecular architecture on fragments, cells expressing them, diversity functions, recent advances. With this review, aim up‐to‐date analysis processes triggered cell types health disease contexts.

Language: Английский

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Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 21, 2023

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing understanding for the donor immune cell composition and its dynamic changes during NMP is essential. We aimed a comprehensive characterization of (sub)populations, trafficking cytokine release liver NMP. Single-cell transcriptome profiling human livers prior to, after transplantation shows abundance CXC chemokine receptor 1+/2+ (CXCR1+/CXCR2+) neutrophils, which significantly decreased This paralleled by large efflux passenger leukocytes with neutrophil predominance in perfusate. During NMP, neutrophils shift from pro-inflammatory state towards aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. herein describe dynamics repertoire, phenotypic shifts dominance potentially contribute to inflammatory response. Our findings may serve resource initiate future immune-interventional studies.

Language: Английский

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