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

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

doi:10.1007/s00330-021-08337-3

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

Eur Radiol. 2022 Apr;32(4):2437-2447. doi: 10.1007/s00330-021-08337-3. Epub 2021 Oct 31.

Authors

Luzie A Doemel^{1

2}, Jessica G Santana¹, Lynn J Savic^{1

2

3}, Fabian M Laage Gaupp¹, Tabea Borde^{1

4}, Alexandra Petukhova-Greenstein^{1

2}, Ahmet S Kucukkaya^{1

2}, Isabel T Schobert^{1

2}, Charlie A Hamm^{2

5}, Bernhard Gebauer², John J Walsh⁶, Irvin Rexha^{1

2}, Fahmeed Hyder^{1

6

7}, MingDe Lin^{1

8}, David C Madoff^{1

7

9

10

11}, Todd Schlachter¹, Julius Chapiro^{12

13}, Daniel Coman^{1

7}

Affiliations

¹ Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
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.
³ Berlin Institute of Health, 10178, Berlin, Germany.
⁴ Department of Diagnostic and Interventional Radiology, Klinikum Rechts Der Isar, Technische Universitat München, Munich, Germany.
⁵ Institute for Diagnostic Radiology and Neuroradiology, Greifswald University Hospital, Ferdinand-Sauerbruch-Strasse, 17475, Greifswald, Germany.
⁶ Department of Biomedical Engineering, School of Engineering & Applied Science, 17 Hillhouse Avenue, New Haven, CT, 06510, USA.
⁷ Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
⁸ Visage Imaging, Inc., San Diego, CA, 92130, USA.
⁹ Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, 06510, USA.
¹⁰ Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
¹¹ Smilow Cancer Hospital Care Center - North Haven, 6 Devine Street, Fl 2, North Haven, CT, 06473, USA.
¹² Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. j.chapiro@googlemail.com.
¹³ Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. j.chapiro@googlemail.com.

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 (pH_e) 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: pH_e mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pH_e 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 pH_e 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 pH_e 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).

Keywords: Carcinoma, hepatocellular; Chemoembolization, therapeutic; Immunohistochemistry; Rabbits; Tumor microenvironment.

MeSH terms

Animals
Carcinoma, Hepatocellular* / pathology
Chemoembolization, Therapeutic* / methods
Doxorubicin
Ethiodized Oil
Liver Neoplasms* / pathology
Rabbits
Tumor Microenvironment

Substances

Ethiodized Oil
Doxorubicin

Abstract

MeSH terms

Substances

Grants and funding