Imaging, Pathology, and Immune Correlates in the Woodchuck Hepatic Tumor Model

Abstract

Michal Mauda-Havakuk,1 Andrew S Mikhail,1 Matthew F Starost,2 Elizabeth C Jones,3 Baktiar Karim,4 David E Kleiner,5 Ari Partanen,1 Juan A Esparza-Trujillo,1 Ivane Bakhutashvili,1 Paul G Wakim,6 Michael T Kassin,1 Andrew L Lewis,7 John W Karanian,1 Bradford J Wood,8 William F Pritchard1 1Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 2Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA; 3Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 4National Cancer Institute, National Institutes of Health, Frederick, MD, USA; 5Center for Cancer Research, Clinical Center, National Cancer Institute, Bethesda, MD, USA; 6Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD, USA; 7Biocompatibles UK Ltd (a BTG International Group Company), Camberley, UK; 8Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering and National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, MD, USACorrespondence: William F PritchardCenter for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Room 3N320B, MSC 1182, Bethesda, MD, 20892, USATel [phone]Fax [phone]Email [email protected]: Woodchucks chronically infected with woodchuck hepatitis virus (WHV), which resembles human hepatitis B virus, develop spontaneous hepatic tumors and may be an important biological and immunological model for human HCC. Nonetheless, this model requires further validation to fully realize its translational potential.Methods: Woodchucks infected at birth with WHV that had developed HCC (n=12) were studied. Computed tomography, ultrasound, and magnetic resonance imaging were performed under anesthesia. LI-RADS scoring and correlative histologic analysis of sectioned tissues were performed. For immune characterization of tumors, CD3 (T cells), CD4 (T helpers), NCAM (Natural killers), FOXP3 (T-regulatory), PDL-1 (inhibitory checkpoint protein), and the human hepatocellular carcinoma (HCC) biomarker alpha-fetoprotein (AFP) immunohistochemical stains were performed.Results: Forty tumors were identified on imaging of which 29 were confirmed to be HCC with 26 categorized as LR-4 or 5. The remainder of the tumors had benign histology including basophilic foci, adenoma, and lipidosis as well as pre-malignant dysplastic foci. LR-4 and LR-5 lesions showed high sensitivity (90%) and specificity (100%) for malignant and pre-malignant tumors. Natural killers count was found to be 2– 5 times lower in tumors relative to normal parenchyma while other immune cells were located in the periphery of tumors. Tumors expressed AFP and did not express PD-L1.Conclusion: Woodchucks chronically infected with WHV developed diverse hepatic tumor types with diagnostic imaging, pathology, and immune patterns comparable to that in humans. This unique animal model may provide a valuable tool for translation and validation of novel image-guided and immune-therapeutic investigations.Keywords: carcinoma, hepatocellular, radiology, interventional oncology, immunotherapy, models, animal, tumor microenvironment

Keywords

• carcinoma
• hepatocellular radiology
• interventional oncology immunotherapy models
• animal tumor microenvironment