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Comparison of metabolic and immunologic responses to transarterial chemoembolization with different chemoembolic regimens in a rabbit VX2 liver tumor model

  • Gastrointestinal
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objectives

The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model.

Methods

VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann–Whitney U test.

Results

pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups.

Conclusions

The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue.

Key Points

• Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025).

• Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen.

• Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).

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Abbreviations

APC:

Antigen-presenting cells

BIRDS:

Biosensor Imaging of Redundant Deviation in Shifts

cTACE:

Conventional TACE

DEE-TACE:

TACE with drug-eluting embolics

HCC:

Hepatocellular carcinoma

IHC:

Immunohistochemistry

pHe :

Extracellular pH

PI:

Positivity index

TACE:

Transarterial chemoembolization

TME:

Tumor microenvironment

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Acknowledgements

We thank Christi Hawley, Marina Mammarian, Stephanie Thorne, Vasily Pekurovsky, and Jonathan Tefera for their support in animal care and handling.

Funding

This study was supported by the following grants: NIH (R01 CA206180 and R01 EB023366) and the Society of Interventional Oncology (19–001324). Research reported in this article was also supported by the Yale Liver Center Microscopy Core. JW was supported in part by T32GM-007205 (Yale MSTP).

Author information

Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Luzie A. Doemel, Jessica G. Santana, Lynn J. Savic, Fabian M. Laage Gaupp, Tabea Borde, Alexandra Petukhova-Greenstein, Ahmet S. Kucukkaya, Isabel T. Schobert, Irvin Rexha, Fahmeed Hyder, MingDe Lin, David C. Madoff, Todd Schlachter, Julius Chapiro & Daniel Coman

  2. Department of Diagnostic and Interventional Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, 10117, Berlin, Germany

    Luzie A. Doemel, Lynn J. Savic, Alexandra Petukhova-Greenstein, Ahmet S. Kucukkaya, Isabel T. Schobert, Charlie A. Hamm, Bernhard Gebauer & Irvin Rexha

  3. Berlin Institute of Health, 10178, Berlin, Germany

    Lynn J. Savic

  4. Department of Diagnostic and Interventional Radiology, Klinikum Rechts Der Isar, Technische Universitat München, Munich, Germany

    Tabea Borde

  5. Institute for Diagnostic Radiology and Neuroradiology, Greifswald University Hospital, Ferdinand-Sauerbruch-Strasse, 17475, Greifswald, Germany

    Charlie A. Hamm

  6. Department of Biomedical Engineering, School of Engineering & Applied Science, 17 Hillhouse Avenue, New Haven, CT, 06510, USA

    John J. Walsh & Fahmeed Hyder

  7. Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Fahmeed Hyder, David C. Madoff, Julius Chapiro & Daniel Coman

  8. Visage Imaging, Inc., San Diego, CA, 92130, USA

    MingDe Lin

  9. Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, 06510, USA

    David C. Madoff

  10. Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    David C. Madoff

  11. Smilow Cancer Hospital Care Center - North Haven, 6 Devine Street, Fl 2, North Haven, CT, 06473, USA

    David C. Madoff

Authors
  1. Luzie A. Doemel
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  2. Jessica G. Santana
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Corresponding author

Correspondence to Julius Chapiro.

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Guarantor

The scientific guarantor of this study is Julius Chapiro, MD.

Conflict of interest

The co-author MingDe Lin is a Visage Imaging, Inc., employee and stock holder. MingDe Lin is an Executive Councilor for Tau Beta Pi Association, Inc.

The other authors declare no competing interests.

Statistics and biometry

Lawrence Staib, PhD, Yale School of Medicine, and Dr. rer. nat. Konrad Neumann, Institute for Biometry and Clinical Epidiomology of the Charite Universitätsmedizin Berlin, kindly provided statistical advice for this manuscript.

Informed consent

Approval from the institutional animal care committee was obtained.

Ethical approval

Institutional Review Board approval was not required because no patients were included in this study.

Study subjects or cohorts overlap

Data from a subgroup of animals were used for a published poster “Characterization of liver tumor microenvironment after treatment with different embolic materials using non-invasive molecular imaging of extracellular pH” on the conference of the Society of Interventional Oncology in 2020. Furthermore, data derived from experiments with a subset of animals (n = 12) were used in previous publications “Molecular Imaging of Extracellular Tumor pH to Reveal Effects of Locoregional Therapy on Liver Cancer Microenvironment” by Savic LJ, Schobert IT, Peters D, et al. published in Clinical Cancer Research in 2020 and “Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?” by Savic LJ, Doemel LA, Schobert IT, et al. published in Radiology in 2020.

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Luzie A. Doemel and Jessica G. Santana contributed equally to this work and therefore share first authorship

Julius Chapiro and Daniel Coman shared contribution as senior authors

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Doemel, L.A., Santana, J.G., Savic, L.J. et al. Comparison of metabolic and immunologic responses to transarterial chemoembolization with different chemoembolic regimens in a rabbit VX2 liver tumor model. Eur Radiol 32, 2437–2447 (2022). https://doi.org/10.1007/s00330-021-08337-3

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