Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential DOI Creative Commons
Vladan Milošević, Arne Östman

Upsala Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 129, P. e10710 - e10710

Published: May 24, 2024

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as key component of the tumour microenvironment (TME). known to play an important role in maintaining and remodelling extracellular matrix (ECM) stroma, supporting cancer progression inhibiting immune system’s response against cells. This review aims summarize immunomodulatory roles CAFs, particularly focussing on their T-cell suppressive effects. have several ways by which they can affect tumour’s (TIME). For example, interactions with macrophages dendritic cells (DCs) create immunosuppressive milieu that indirectly anticancer immunity enable evasion. In addition, number recent studies confirmed CAF-mediated direct effects capacity through ECM remodelling, promoting expression checkpoints, cytokine secretion release vesicles. The consequential impact CAFs function is then reflected affecting proliferation apoptosis, migration infiltration, differentiation exhaustion. Emerging evidence highlights existence specific CAF subsets distinct capabilities modulate landscape TME various cancers, suggesting possibility exploitation possible prognostic biomarkers therapeutic targets.

Language: Английский

Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation DOI Creative Commons

Yang Gao,

Jianan Li,

Wenfeng Cheng

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

40
Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer DOI Creative Commons
Katey S.S. Enfield, Emma Colliver, Claudia Lee

et al.

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(6), P. 1018 - 1047

Published: April 6, 2024

Abstract Understanding the role of tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs treatment-naïve early-stage using imaging mass cytometry TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for plasma B immune-excluded squamous cell carcinomas (LUSC). Immune-low were associated fibroblast barriers immune infiltration. The fourth archetype, characterized by sparse lymphocytes high tumor-associated neutrophil (TAN) infiltration, had spatially separated from vasculature exhibited low intratumor heterogeneity. TAN-high LUSC frequent PIK3CA mutations. tumors harbored recently expanded metastasis-seeding subclones a shorter disease-free survival independent stage. These findings delineate genomic, immune, physical surveillance implicate neutrophil-rich metastasis. Significance: This provides novel insights into organization TME context immunogenicity, heterogeneity, evolution. Pairing evolutionary history resolved suggests mechanistic hypotheses progression metastasis implications outcome treatment. article featured Selected Articles Issue, p. 897

Language: Английский

Citations

32
Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome DOI Creative Commons
Layla Mathieson, Lilian Koppensteiner, David A. Dorward

et al.

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 130(11), P. 1758 - 1769

Published: April 6, 2024

Abstract Background Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations CAFs, which can influence prognosis and treatment efficacy. We describe subtypes CAFs NSCLC. Methods Primary human NSCLC resections were assessed by flow cytometry multiplex immunofluorescence for markers fibroblast activation allowed identification CAF subsets. Survival data analysed our cohort consisting 163 patients to understand prognostic significance Results identified five populations, termed S1-S5. CAF-S5 represents previously undescribed population, express FAP PDPN but lack myofibroblast marker αSMA, whereas CAF-S1 populations all three. spatially further from tumour regions then scRNA demonstrate an inflammatory phenotype. The presence or is correlated worse survival outcome NSCLC, despite curative resection, highlighting importance TCGA suggest predominance has poor across several types. Conclusion This study describes novel subset where its correlates outcome.

Language: Английский

Citations

22
Classifying cancer-associated fibroblasts—The good, the bad, and the target DOI
Lena Cords, Natalie de Souza, Bernd Bodenmiller

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(9), P. 1480 - 1485

Published: Sept. 1, 2024

Language: Английский

Citations

19
Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures DOI Creative Commons
Florent Peyraud,

Jean-Philippe Guégan,

Christophe Rey

et al.

Cell Reports Medicine, Journal Year: 2025, Volume and Issue: unknown, P. 101934 - 101934

Published: Feb. 1, 2025

Highlights•mTLSs are predictive of response to ICIs in NSCLC•Two CAF subsets within the TME key determinants primary resistance ICIs•FAP+αSMA+ CAFs correlate with inflammatory and exhaustion CD8+ T cells•MYH11+αSMA+ favor an immunosuppressive CD4+ Treg cell infiltrationSummaryEffectiveness immune checkpoint inhibitors (ICIs) non-small lung cancer (NSCLC) has been linked presence mature tertiary lymphoid structures (mTLSs) tumor microenvironment (TME). However, only a subset mTLS-positive NSCLC derives benefit, thus highlighting need unravel ICI determinants. The comprehensive analysis ICI-treated patients (n = 509) from Bergonié Institute Profiling (BIP) study (NCT02534649) reveals that mTLSs correlates improved clinical outcomes, independently programmed death ligand 1 (PD-L1) expression genomic features. Employing spatial transcriptomics alongside multiplex immunofluorescence (mIF), we show two distinct cancer-associated fibroblasts (CAFs) essential factors mediating NSCLC. These associated exclusion, exhaustion, increased regulatory infiltration, underscoring TME. Our highlights pivotal role specific thwarting ICIs, proposing new therapeutic targets enhance immunotherapy efficacy.Graphical abstract

Language: Английский

Citations

4
Integrative analysis of Ewing’s sarcoma reveals that the MIF-CD74 axis is a target for immunotherapy DOI Creative Commons
Fangzhou He, Jiuhui Xu, Fanwei Zeng

et al.

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 13, 2025

Ewing's sarcoma (EwS), a common pediatric bone cancer, is associated with poor survival due to lack of therapeutic targets for immunotherapy or targeted therapy. Therefore, more effective treatment options are urgently needed. Since novel immunotherapies may address this need, we performed an integrative analysis involving single-cell RNA sequencing, cell function experiments, and humanized models dissect the immunoregulatory interactions in EwS identify strategies optimizing immunotherapeutic efficacy. infiltrated by immunosuppressive myeloid populations, T B lymphocytes, natural killer cells. We found that SLC40A1 C1QA macrophages were prognosis, whereas CD8+ T-cell infiltration was good prognosis. A comparative paired samples revealed tumors chemotherapeutic response, presented increased antigen presentation reduced release protumor cytokines, cells cytotoxicity exhaustion. An interaction vast network identified MIF-CD74 as crucial target can simultaneously promote M2 polarization inhibit infiltration. Importantly, MIF blockade effectively reshaped tumor immune microenvironment, turning cold hot inhibiting growth. Our MIF/CD74 axis promising Ewing provides rationale immunotherapy.

Language: Английский

Citations

3
A novel HVEM-Fc recombinant protein for lung cancer immunotherapy DOI Creative Commons

Yu Yao,

B. Li, Jing Wang

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Feb. 20, 2025

The ubiquitously expressed transmembrane protein, Herpesvirus Entry Mediator (HVEM), functions as a molecular switch, capable of both activating and inhibiting the immune response depending on its interacting ligands. HVEM-Fc is novel recombinant fusion protein with potential to eradicate tumor cells. anti-tumor efficacy was evaluated in C57BL/6 mice-bearing lung cancer models: syngeneic model an orthotopic mouse cancer. Additionally, patient-derived organoids were employed conjunction T cell co-culture systems. To investigate underlying mechanisms, comprehensive array techniques utilized, including single-cell RNA sequencing, spatial transcriptomics, bulk flow cytometry. Furthermore, effects combination Programmed Death-1 (PD-1) inhibitors assessed. Finally, depletion antibodies used elucidate mechanisms action. In vivo, 1 mg/kg demonstrated effective inhibition growth metastasis mice bearing KP Multi-omics analysis showed that induced immune-stimulatory microenvironment. Notably, PD-1 inhibitor most potent growth. vitro, validated cells through activation non-small (NSCLC) models. Our data demonstrate exerts strong signal augments prolongs T-cell activity murine models human NSCLC organoid Moreover, yields outcomes.

Language: Английский

Citations

3
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment DOI
Douglas Hanahan, Olivier Michielin, Mikaël J. Pittet

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 24, 2024

Language: Английский

Citations

13
Prognostic implications and therapeutic opportunities related to CAF subtypes in CMS4 colorectal cancer: insights from single-cell and bulk transcriptomics DOI Creative Commons

Mengke Ma,

Chu Jin, Changhua Zhuo

et al.

APOPTOSIS, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Language: Английский

Citations

2
Cancer-associated fibroblasts promote EGFR-TKI resistance via the CTHRC1/glycolysis/H3K18la positive feedback loop DOI Creative Commons
Chen Zhang,

Wenxin Zhou,

Hai Xu

et al.

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of lung cancer. Cancer associated fibroblasts (CAFs) play key role promoting anti-cancer therapies. This study identified subpopulation CAFs characterized by overexpression collagen triple helix repeat-containing 1 (CTHRC1) through single-cell RNA sequencing cancer patients undergoing EGFR-TKI treatment. These CTHRC1+ were enriched drug-resistant tumors. Mechanistically, enhance glycolytic activity cells activating TGF-β/Smad3 signaling pathway. Excess lactate produced process glycolysis further upregulates CTHRC1 expression histone lactylation, creating positive feedback loop that sustains resistance. The also demonstrated Gambogenic Acid, natural compound, can disrupt this loop, thereby improving efficacy therapy. Additionally, presence tumor tissues could serve as biomarker for predicting response therapy and patient prognosis. Overall, highlights significant suggests targeting be promising strategy overcome drug

Language: Английский

Citations

2