Lenvatinib Mitigates Transarterial Embolization-Induced Polarization of Tumor-Associated Macrophages in a Rat Hepatocellular Carcinoma Model

Abstract

Purpose: To investigate the effect of transarterial embolization (TAE) on macrophage polarization and the modulatory effect of lenvatinib when used in combination with TAE in a rat hepatocellular carcinoma model.

Materials and methods: A N1S1-bearing orthotopic rat model was subjected to TAE and administered 5 mg/kg of lenvatinib. CD8⁺, CD68⁺, and CD206⁺ cells were examined in 4 groups: sham (n = 5), lenvatinib (n = 5), TAE (n = 5), and combination of TAE and lenvatinib (n = 5). Transcriptome analysis was performed to assess gene expression related to macrophage polarization in the sham, TAE, and combination groups. An in vitro coculture experiment with bone marrow-derived macrophages was performed to identify lenvatinib target in macrophage polarization.

Results: There were no significant differences in the number of CD8⁺ and CD68⁺ cells among the 4 groups. Tumor-associated macrophage positivity for CD206 was significantly higher in the TAE group (58.1 ± 20.9) than in the sham (11.2 ± 14.3; P < .001) and combination (27.1 ± 19.7; P = .003) groups. In the transcriptome analysis, compared with the genes in the sham group, 5 macrophage polarization-related genes, including St6gal1, were upregulated by more than 1.5 fold in the TAE group and downregulated by more than 1.5 fold in the combination group. The coculture experiment showed that lenvatinib did not affect macrophages but affected N1S1 cells, leading to macrophage polarization.

Conclusions: TAE-induced M2 macrophage polarization. Lenvatinib administration with TAE could reprogram macrophage polarization, improving tumor immune microenvironment.