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Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Erika Y. Faraoni, View ORCID ProfileNirav C. Thosani, Baylee O’Brien, Lincoln N. Strickland, Victoria Mota, Jarod Chaney, Putao Cen, Julie Rowe, Jessica Cardenas, View ORCID ProfileKyle L. Poulsen, View ORCID ProfileCurtis J. Wray, View ORCID ProfileJennifer Bailey-Lundberg
doi: https://doi.org/10.1101/2022.01.07.475451
Erika Y. Faraoni
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Nirav C. Thosani
2Center for Interventional Gastroenterology at UTHealth (iGUT), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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  • ORCID record for Nirav C. Thosani
Baylee O’Brien
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Lincoln N. Strickland
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Victoria Mota
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Jarod Chaney
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Putao Cen
3Division of Oncology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Julie Rowe
3Division of Oncology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Jessica Cardenas
4Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Kyle L. Poulsen
5Department of Anesthesiology, Center for Perioperative Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Curtis J. Wray
4Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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Jennifer Bailey-Lundberg
1Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
2Center for Interventional Gastroenterology at UTHealth (iGUT), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
5Department of Anesthesiology, Center for Perioperative Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030
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  • For correspondence: Jennifer.M.Bailey@uth.tmc.edu
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ABSTRACT

Background and Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies.

Methods To test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis.

Results RFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses.

Conclusions These data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease.

Figure

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Co-first authors

  • CONFLICT OF INTEREST: The authors have no conflicts of interest to disclose.

  • GRANT SUPPORT: The RPPA Core facility at MDAnderson is funded by CA16672. J.B.L received funding from the Texas Medical Center Digestive Disease Center Pilot Award 2P30DK056338-16, a grant from the National Pancreas Foundation and Pathway to Leadership Grant from the Pancreatic Cancer Action Network and American Association for Cancer Research.

  • ABBREVIATIONS

    RFA
    Radiofrequency ablation
    TME
    Tumor microenvironment
    EUS
    Endoscopic ultrasound
    CAF
    Cancer associated fibroblasts
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    Posted January 10, 2022.
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    Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer
    Erika Y. Faraoni, Nirav C. Thosani, Baylee O’Brien, Lincoln N. Strickland, Victoria Mota, Jarod Chaney, Putao Cen, Julie Rowe, Jessica Cardenas, Kyle L. Poulsen, Curtis J. Wray, Jennifer Bailey-Lundberg
    bioRxiv 2022.01.07.475451; doi: https://doi.org/10.1101/2022.01.07.475451
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    Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer
    Erika Y. Faraoni, Nirav C. Thosani, Baylee O’Brien, Lincoln N. Strickland, Victoria Mota, Jarod Chaney, Putao Cen, Julie Rowe, Jessica Cardenas, Kyle L. Poulsen, Curtis J. Wray, Jennifer Bailey-Lundberg
    bioRxiv 2022.01.07.475451; doi: https://doi.org/10.1101/2022.01.07.475451

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