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Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?
Savic, Lynn Jeanette; Doemel, Luzie A; Schobert, Isabel Theresa; Montgomery, Ruth Rebecca; Joshi, Nikhil; Walsh, John James; Santana, Jessica; Pekurovsky, Vasily; Zhang, Xuchen; Lin, MingDe; Adam, Lucas; Boustani, Annemarie; Duncan, James; Leng, Lin; Bucala, Richard John; Goldberg, S Nahum; Hyder, Fahmeed; Coman, Daniel; Chapiro, Julius.
Afiliação
  • Savic LJ; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Doemel LA; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Schobert IT; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Montgomery RR; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Joshi N; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Walsh JJ; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Santana J; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Pekurovsky V; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Zhang X; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Lin M; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Adam L; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Boustani A; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Duncan J; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Leng L; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Bucala RJ; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Goldberg SN; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Hyder F; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Coman D; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
  • Chapiro J; From the Department of Radiology and Biomedical Imaging (L.J.S., L.A.D., I.T.S., J.J.W., J.S., M.D.L., L.A., A.B., J.D., F.H., D.C., J.C.), Department of Internal Medicine, Section of Rheumatology (R.R.M., L.L., R.J.B.), Department of Immunobiology (N.J.), and Department of Pathology (V.P., X.Z.), Y
Radiology ; 296(3): 575-583, 2020 09.
Article em En | MEDLINE | ID: mdl-32633675
ABSTRACT
Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imageamento por Ressonância Magnética / Carcinoma Hepatocelular / Imagem Molecular / Neoplasias Hepáticas Experimentais Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imageamento por Ressonância Magnética / Carcinoma Hepatocelular / Imagem Molecular / Neoplasias Hepáticas Experimentais Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article