YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer DOI Creative Commons
Hongtao Song, Tong Lü, Donghui Han

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(22), P. 3728 - 3742

Published: Aug. 13, 2024

Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically "cold" tumor microenvironment and considered a promising target enhance immunotherapy response. In this study, we aimed reveal mechanisms regulating CAF plasticity identify potential strategies switch CAFs from protumorigenic antitumor phenotypes ICB efficacy in prostate cancer. Integration four single-cell RNA sequencing datasets defined CAFs, RNA-seq, flow cytometry, organoid model demonstrated functions two subtypes. Extracellular matrix-associated (ECM-CAF) promoted collagen deposition cell progression, lymphocyte-associated (Lym-CAF) exhibited an phenotype induced infiltration activation CD8+ T cells. YAP1 activity regulated ECM-CAF phenotype, silencing switching Lym-CAFs. NF-κB p65 was core transcription factor Lym-CAF subset, inhibited nuclear translocation p65. Selective depletion ECM-CAFs vivo T-cell enhanced therapeutic effects anti-PD-1 treatment on Overall, study revealed mechanism identity highlighted strategy for altering subtype suppress growth increase sensitivity ICB. Significance: regulates cancer-associated fibroblast can be targeted that promotes extracellular matrix tumor-suppressive stimulates immunity efficacy.

Language: Английский

Targeting the devil: Strategies against cancer-associated fibroblasts in colorectal cancer DOI
Yuting Chen, Zhiyong Liang, Maode Lai

et al.

Translational research, Journal Year: 2024, Volume and Issue: 270, P. 81 - 93

Published: April 16, 2024

Language: Английский

Citations

13
POSTN+cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma DOI Creative Commons
Hao Wang, Yuan Liang, Zheng Liu

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(7), P. e008721 - e008721

Published: July 1, 2024

Objective Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis. Design In this study, to systematically investigate characteristics cancer-associated fibroblast (CAF) subsets and dynamic communication among tumor microenvironment (TME) components regulated by CAF subsets, we generated an atlas compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq multiplexed immunofluorescence identify specific TME that determine efficacy patients. Results Our findings highlight pivotal role POSTN + CAFs as potent response barriers at locations, they hinder effective T-cell infiltration decrease immunotherapy. Additionally, elucidated interplay between SPP1 macrophages, whereby former recruits latter triggers increased expression via IL-6/STAT3 signaling pathway. Moreover, demonstrated correlation revealing immunosuppressive limits response. Notably, found patients elevated levels both macrophages achieved less therapeutic benefit cohort. Conclusion research elucidates light particular subset resistance, emphasizing potential targeting subpopulations improve responses

Language: Английский

Citations

13
Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis DOI Creative Commons
Sarah Ash, Rebecca Orha, Holly Mole

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(2), P. e008608 - e008608

Published: Feb. 1, 2024

Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack suitable tumor-specific antigens and immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity persistence. We hypothesized targeting endosialin (CD248) receptor, strongly expressed tumor-associated pericytes perivascular cancer-associated fibroblasts, would circumvent these challenges offer an exciting for therapy due to close proximity target vasculature, expression in normal tissues phenotype observed knockout mice. generated endosialin-directed E3K from three immunocompetent mouse strains, BALB/c, FVB/N C57BL/6. composition (CD4+/CD8+ ratio), vitro against endosialin+ endosialin- cells, expansion vivo syngeneic models as well tumor-naive healthy wounded mice tumor-bearing was assessed. were active both human endosialin+, but not endosialin-, cells. Adoptively transferred exhibited no mice, wildtype or wound healing models, demonstrating absence off-target on-target/off-tumor activity. By contrast, adoptive transfer into C57BL/6 bearing breast lung cancer lines depleted stroma resulting increased necrosis, reduced growth a substantial impairment metastatic outgrowth. Together data highlight viable stromal closely associated vasculature avoids having navigate harsh immunosuppressive microenvironment. Further, ability recognize makes humanized optimized CAR promising candidate clinical development applicable broad range types.

Language: Английский

Citations

12
Single-cell RNA sequencing in melanoma: what have we learned so far? DOI Creative Commons
Su Yin Lim, Helen Rizos

EBioMedicine, Journal Year: 2024, Volume and Issue: 100, P. 104969 - 104969

Published: Jan. 21, 2024

Over the past decade, there have been remarkable improvements in treatment and survival rates of melanoma patients. Treatment resistance remains a persistent challenge, however, is partly attributable to intratumoural heterogeneity. Melanoma cells can transition through series phenotypic transcriptional cell states that vary invasiveness responsiveness. The diverse stromal immune contexture tumour microenvironment also contributes heterogeneity disparities response Recent advances single-cell sequencing technologies enabled more detailed understanding underlying programs regulate diversity behaviour. In this review, we examine concept challenges it poses achieving long-lasting responses. We focus on significance next generation advancing our unique insights gained from studies.

Language: Английский

Citations

11
YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer DOI Creative Commons
Hongtao Song, Tong Lü, Donghui Han

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(22), P. 3728 - 3742

Published: Aug. 13, 2024

Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically "cold" tumor microenvironment and considered a promising target enhance immunotherapy response. In this study, we aimed reveal mechanisms regulating CAF plasticity identify potential strategies switch CAFs from protumorigenic antitumor phenotypes ICB efficacy in prostate cancer. Integration four single-cell RNA sequencing datasets defined CAFs, RNA-seq, flow cytometry, organoid model demonstrated functions two subtypes. Extracellular matrix-associated (ECM-CAF) promoted collagen deposition cell progression, lymphocyte-associated (Lym-CAF) exhibited an phenotype induced infiltration activation CD8+ T cells. YAP1 activity regulated ECM-CAF phenotype, silencing switching Lym-CAFs. NF-κB p65 was core transcription factor Lym-CAF subset, inhibited nuclear translocation p65. Selective depletion ECM-CAFs vivo T-cell enhanced therapeutic effects anti-PD-1 treatment on Overall, study revealed mechanism identity highlighted strategy for altering subtype suppress growth increase sensitivity ICB. Significance: regulates cancer-associated fibroblast can be targeted that promotes extracellular matrix tumor-suppressive stimulates immunity efficacy.

Language: Английский

Citations

11