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10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis

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Abstract

Purpose

The application of nanosecond pulsed electric fields (nsPEFs) could be an effective therapeutic strategy for peritoneal metastasis (PM) from colorectal cancer (CRC). The aim of this study was to evaluate in vitro the sensitivity of CT-26 CRC cells to nsPEFs in combination with chemotherapeutic agents, and to observe the subsequent in vivo histologic response.

Methods

In vitro cellular assays were performed to assess the effects of exposure to 1, 10, 100, 500 and 1000 10 ns pulses in a cuvette or bi-electrode system at 10 and 200 Hz. nsPEF treatment was applied alone or in combination with oxaliplatin and mitomycin. Cell death was detected by flow cytometry, and permeabilization and intracellular calcium levels by fluorescent confocal microscopy after treatment. A mouse model of PM was used to investigate the effects of in vivo exposure to pulses delivered using a bi-electrode system; morphological changes in mitochondria were assessed by electron microscopy. Fibrosis was measured by multiphoton microscopy, while the histological response (HR; hematoxylin–eosin–safran stain), proliferation (KI67, DAPI), and expression of immunological factors (CD3, CD4, CD8) were evaluated by classic histology.

Results

10 ns PEFs exerted a dose-dependent effect on CT-26 cells in vitro and in vivo, by inducing cell death and altering mitochondrial morphology after plasma membrane permeabilization. In vivo results indicated a specific CD8+ T cell immune response, together with a strong HR according to the Peritoneal Regression Grading Score (PRGS).

Conclusions

The effects of nsPEFs on CT-26 were confirmed in a mouse model of CRC with PM.

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Abbreviations

nsPEFs:

Nanosecond pulsed electric fields

PM:

Peritoneal metastasis

CRC:

Colorectal cancer

HES:

Hematoxylin and eosin stain

HIPEC:

Hyperthermic intraperitoneal chemotherapy

CT:

Control

ns:

Non-significant

PIPAC:

Pressurized Intraperitoneal Aerosol Chemotherapy

PRGS:

Peritoneal Regression Grading Score

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Acknowledgements

We thank R Bachelot for his interest during his master for multiphoton microscopy/HIPEC, Pr. M Pocard (CART Inserm U965) for the technical support regarding cell culture and P Leveque and D Arnaud-Cormos for lending the exposure system. This work benefited from government support managed by the National Research Agency under the Investments for the future program with the reference ANR-10-LABX-0074-01 Sigma-LIM, and funds from the Limoges Hospital committee for research orientation in oncology (CORC « Carcinopulse » 2018). This research was conducted in the scope of GDR HappyBio (CNRS) and LEA-EBAM, a European Associated Laboratory titled “Pulsed Electric Fields Applications in Biology and Medicine”.

Funding

This work benefited from government support managed by the National Research Agency under the Investments for the future program with the reference ANR-10-LABX-0074–01 Sigma-LIM, and was also supported by funds from the Limoges Hospital committee for research orientation in oncology (CORC « Carcinopulse» 2018).

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Authors and Affiliations

  1. Digestive Surgery Department, Limoges University Hospital, Limoges, France

    A. Taibi & S. Durand-Fontanier

  2. Univ. Limoges, CNRS, XLIM, UMR 7252, 87000, Limoges, France

    A. Taibi, M.-L. Perrin, J. Albouys, J. Jacques, C. Yardin, S. Durand-Fontanier & S. M. Bardet

  3. Gastroenterology Department, Limoges University Hospital, Limoges, France

    J. Albouys & J. Jacques

  4. Cytology and Histology Department, Limoges University Hospital, Limoges, France

    C. Yardin

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  1. A. Taibi
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  3. J. Albouys
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  4. J. Jacques
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  6. S. Durand-Fontanier
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  7. S. M. Bardet
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Contributions

Study conception and design: AT, SDF, SB. Provision of study materials or patients: AT, M-LP, SB. Data and statistical analysis and interpretation: AT and SB. Drafting and editing of manuscript: all authors. Critical manuscript review and approval of final version: all authors.

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Correspondence to S. M. Bardet.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Research involving human participants and/or animals

The use of animals was approved by the local Ethics and Animal Care Committee (registration number: 2017102611003706, Sylvia M Bardet). All animal care and experimental procedures were conducted in conformity with 2013 French legislation, which is in accordance with European Community guidelines (directive 2010/63/UE for the Care and Use of Laboratory Animals).

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For this study, we obtained the consent for all the patients

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12094_2020_2525_MOESM1_ESM.tiff

Supplementary file1 Supplementary Figure 1: Dose-dependant results for mitomycin and oxaliplatin. Cell viability was assessed by MTT assays after 24 h (white dots) and 48 h (black dots) of treatment (data for 72 h are not shown). The IC50 values for the 24-h treatment were 17.5 µg/ml for mitomycin and 200 µg/ml for oxaliplatin. (TIFF 2275 KB)

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Taibi, A., Perrin, ML., Albouys, J. et al. 10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis. Clin Transl Oncol 23, 1220–1237 (2021). https://doi.org/10.1007/s12094-020-02525-1

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  • DOI: https://doi.org/10.1007/s12094-020-02525-1

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