Transcriptomic Profiling of the Immune Response in Orthotopic Pancreatic Tumours Exposed to Combined Boiling Histotripsy and Oncolytic Reovirus Treatment

Background: Boiling histotripsy (BH) uses high-amplitude, short-pulse focused ultrasound to disrupt tissue mechanically. Oncolytic virotherapy using reovirus has shown modest clinical benefit in pancreatic cancer patients. Here, reovirus and BH were used to treat pancreatic tumours, and their effect...

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Published in:Pharmaceutics Vol. 17; no. 8; p. 949
Main Authors: Mouratidis, Petros, Ferreira, Ricardo C., Anbalagan, Selvakumar, Chauhan, Ritika, Rivens, Ian, ter Haar, Gail
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 22.07.2025
MDPI
Subjects:
B cells
Broadband transmission
Cancer research
Cancer therapies
Cell death
Chemokines
Chemotherapy
Cytokines
focused ultrasound
Histology
histotripsy
Immune response
Immunotherapy
Medical prognosis
Medical research
Metastasis
Oncolytic viruses
Pancreatic cancer
reovirus
T cells
therapeutic ultrasound
Tumors
Ultrasonic imaging
United Kingdom
Washington, D.C
United Kingdom > UK
United States > US
Oncolytic viruses
therapeutic ultrasound
pancreatic cancer
TAP complex
histotripsy
reovirus
immunotherapy
focused ultrasound
transcriptomic profiling
ISSN:1999-4923, 1999-4923
Online Access:Get full text
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Summary:Background: Boiling histotripsy (BH) uses high-amplitude, short-pulse focused ultrasound to disrupt tissue mechanically. Oncolytic virotherapy using reovirus has shown modest clinical benefit in pancreatic cancer patients. Here, reovirus and BH were used to treat pancreatic tumours, and their effects on the immune transcriptome of these tumours were characterised. Methods: Orthotopic syngeneic murine pancreatic KPC tumours grown in immune-competent subjects, were allocated to control, reovirus, BH and combined BH and reovirus treatment groups. Acoustic cavitation was monitored using a passive broadband cavitation sensor. Treatment effects were assessed histologically with hematoxylin and eosin staining. Single-cell multi-omics combining whole-transcriptome analysis with the expression of surface-expressed immune proteins was used to assess the effects of treatments on tumoural leukocytes. Results: Acoustic cavitation was detected in all subjects exposed to BH, causing cellular disruption in tumours 6 h after treatment. Distinct cell clusters were identified in the pancreatic tumours 24 h post-treatment. These included neutrophils and cytotoxic T cells overexpressing genes associated with an N2-like and an exhaustion phenotype, respectively. Reovirus decreased macrophages, and BH decreased regulatory T cells compared to controls. The combined treatments increased neutrophils and the ratio of various immune cells to Treg. All treatments overexpressed genes associated with an innate immune response, while ultrasound treatments downregulated genes associated with the transporter associated with antigen processing (TAP) complex. Conclusions: Our results show that the combined BH and reovirus treatments maximise the overexpression of genes associated with the innate immune response compared to that seen with each individual treatment, and illustrate the anti-immune phenotype of key immune cells in the pancreatic tumour microenvironment.
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ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics17080949