Dataset Information

Interrogating the Synergistic Potential of Gemcitabine and Focused Ultrasound–Induced Thermal Ablation in Breast Cancer: Insights from the BR54 Trial via Spatial Transcriptomics

ABSTRACT: Breast tumors frequently exhibit resistance to immunotherapy due to their immunosuppressive tumor microenvironment (TME). Preclinical evidence indicates that combining thermal high-intensity focused ultrasound (T-FUS) with the chemotherapeutic gemcitabine (GEM) can significantly alter this TME, promoting recruitment and activation of antitumor immune cells and facilitating durable, T cell–mediated tumor control. We hypothesize that GEM preconditioning enhances T-FUS-induced inflammatory responses by reducing anti-inflammatory cell abundance in the transition zone, thereby amplifying the infiltration and activation of effector immune cells. Leveraging the ongoing BR54 clinical trial (NCT04796220), we analyzed resected breast cancer specimens, collected approximately 14 days post-T FUS treatment, with or without prior GEM pretreatment. Using NanoString’s CosMx Spatial Molecular Imager and 1000-plex RNA panel, we performed spatially-resolved gene transcription profiling within histologically defined regions, including FUS-induced thermal lesions and adjacent tumor areas. Our analysis focused on quantifying myeloid cell, T cell, and NK cell signatures, evaluating effector molecule gene expression, and assessing immunosuppressive-to-effector cell ratios. Comparative analyses between FUS-treated patient samples (with or without GEM pretreatment) and archival untreated controls, as well as pre- to post-treatment biopsy comparisons, were conducted to evaluate therapy-induced remodeling of the TME. This project aims to elucidate the potential synergistic effects of GEM combined with T-FUS in breast cancer and establish the CosMx platform as a robust tool for integrated spatial multiomics analysis in clinical oncology research.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296517 | GEO | 2026/08/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

Dataset Information

Interrogating the Synergistic Potential of Gemcitabine and Focused Ultrasound–Induced Thermal Ablation in Breast Cancer: Insights from the BR54 Trial via Spatial Transcriptomics

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets