Impact of Chemoembolic Regimen on Immune Cell Recruitment and Immune Checkpoint Marker Expression following Transcatheter Arterial Chemoembolization in a VX2 Rabbit Liver Tumor Model.

ABSTRACT

PURPOSE: To characterize the effects of commonly used transcatheter arterial chemoembolization (TACE) regimens on the immune response and immune checkpoint marker expression using a VX2 rabbit liver tumor model. MATERIALS AND METHODS: Twenty-four VX2 liver tumor-bearing New Zealand white rabbits were assigned to 7 groups (n = 3 per group) undergoing locoregional therapy as follows (a) bicarbonate infusion without embolization, (b) conventional TACE (cTACE) using a water-in-oil emulsion containing doxorubicin mixed 12 with Lipiodol, drug-eluting embolic-TACE with either (c) idarubicin-eluting Oncozene microspheres (40 µm) or (d) doxorubicin-eluting Lumi beads (40-90 µm). For each therapy arm (b-d), a tandem set of 3 animals with additional bicarbonate infusion before TACE was added, to evaluate the effect of pH modification on the immune response. Three untreated rabbits served as controls. Tissue was harvested 24 hours after treatment, followed by digital immunohistochemistry quantification (counts/µm2 ± SEM) of tumor-infiltrating cluster of differentiation 3+ T-lymphocytes, human leukocyte antigen DR type antigen-presenting cells (APCs), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) pathway axis expression. RESULTS: Lumi-bead TACE induced significantly more intratumoral T-cell and APC infiltration than cTACE and Oncozene-microsphere TACE. Additionally, tumors treated with Lumi-bead TACE expressed significantly higher intratumoral immune checkpoint markers compared with cTACE and Oncozene-microsphere TACE. Neoadjuvant bicarbonate demonstrated the most pronounced effect on cTACE and resulted in a significant increase in intratumoral cluster of differentiation 3+ T-cell infiltration compared with cTACE alone. CONCLUSIONS: This preclinical study revealed significant differences in evoked tumor immunogenicity depending on the choice of chemoembolic regimen for TACE.