Rahul Sheth, MD
Disclosure(s): Boston Scientific: Consultant (), Research Grant or Support (); Medtronic: Consultant (); Replimune: Consultant (Ongoing); Siemens: Consultant (Ongoing); Trisalus: Consultant ()
Malea Williams, n/a
Department of Interventional Radiology at The University of Texas MD Anderson Cancer Center
To develop and evaluate the immunologic ramifications of a novel immunotherapy-eluting microsphere following transarterial embolization of orthotopic hepatocellular carcinoma (HCC) tumors in a rat model.
Materials and Methods:
A novel absorbable microsphere (ImmunoBead) was developed to elute the toll-like receptor 7 agonist imiquimod. An HCC model was generated by orthotopic implantation of RH7777 hepatoma cells in Buffalo rats. Animals were then randomized to undergo transarterial embolization with ImmunoBead versus saline sham (n=12 per arm). Three days following intervention, immune profiling was performed using flow cytometry, immunohistochemistry (IHC), Nanostring transcriptomics, and single cell RNA sequencing (scRNAseq). Additionally, the deposition of imiquimod as well as metabolic alterations were visualized using mass spectrometry imaging (MSI).
MSI revealed > 3:1 tumor-to-background deposition of imiquimod within the target tumor. Metabolic analysis revealed decreases in metabolites (glutathione, histamine, and adenosine) within the tumor associated with immunosuppressive microenvironments following ImmunoBead embolization relative to sham. IHC revealed an increase in CD4+ and CD8+ T cells within the tumor following ImmunoBead embolization. These findings were corroborated on flow cytometry which revealed an increase in CD45+CD3+CD8a+ T cells (39% ImmunoBead vs 19% sham, P < 0.05) as well as a decrease in M2 macrophages (CD163+, 9% vs 23%, P < 0.05). scRNAseq revealed an important increase in Batf3+ conventional dendritic cell type 1 (cDC1, P < 0.005) and Irf4+ conventional dendritic cell type 2 (cDC2, P < 0.01) following ImmunoBead embolization relative to sham, key drivers of antigen presentation and adaptive immunity. There was also an increase in the overall cell percentages for CD8+ effector memory T cells and CD8+ activated T cells and a decrease in regulatory T cells following ImmunoBead embolization. Transcriptional profiling of the tumor following ImmunoBead embolization revealed numerous differentially expressed gene pathways indicative of a shift away from immunosuppression, including downregulation of the Wnt/beta-catenin pathway, checkpoint inhibitors including Marco and Ctla4, and immunosuppressive cytokines such as IL6.
Transarterial embolization with ImmunoBead effectively diminished the immunosuppressive liver tumor microenvironment and enhance immunostimulatory signals. Embolization with ImmunoBead is promising approach to augment antitumoral immune mechanisms in HCC.