Multimodal imaging of the tumor microenvironment and biological responses to immune therapy

• Published in: Biomedical microdevices Vol. 20; no. 4; p. 105
• Main Authors: Saucedo, Alexander M., De La Cerda, Jorge, Suami, Hiroo, Serda, Rita E.
• Format: Journal Article
• Language: English
• Published: New York Springer US 03.12.2018; Springer Nature B.V
• Subjects: Adenocarcinoma; Animal models; Biological activity; Biological and Medical Physics; Biomedical Engineering and Bioengineering; Biophysics; Blood vessels; Cancer; CD4 antigen; CD45 antigen; CD8 antigen; Cell density; Cytokines; Density; Electron microscopy; Engineering; Engineering Fluid Dynamics; Extracellular matrix; Fluorescence; Granulocyte colony-stimulating factor; Immune system; Inflammation; Interferon; Interleukin 10; Interleukin 12; Leukocytes; Lymphocytes; Lymphocytes T; Macrophages; Monocytes; Nanotechnology; Perfluorocarbons; Perfusion; Phenotypes; Suppressor cells; Therapy; Tumors; Vascular endothelial growth factor; computed tomography; Interleukin 12; Magnetic resonance imaging; Electron microscopy; Tumor vasculature
• DOI: 10.1007/s10544-018-0347-8
• ISSN: 1387-2176

Beyond heterogeneous cancer cells, the tumor microenvironment includes stromal and immune cells, blood vessels, extracellular matrix and biologically active molecules. Abnormal signaling, uncontrolled proliferation and high interstitial pressure all contribute to a chaotic, non-hierarchical vascular organization. Using an immune competent 4T1 breast adenocarcinoma murine model, this study fully characterizes the architecture and immunocyte milieu of the tumor microenvironment. Heterogeneous vessel distribution, chaotic connectivity, limited perfusion, cancer cell density, immune phenotype, and biological responses to immune therapy are presented. Cancer cell density mirrored the distribution of large, perfusable vessels, both predominately in the tumor periphery. Intratumoral administration of the proinflammatory cytokine IL-12 led to an increase in CD45 + leukocytes, with a specific increase in CD4 + and CD8 + T cells, and a decrease in the percentage of Gr-l lo myeloid-derived suppressor cells. Concomitantly, serum G-CSF, IL-10 and VEGF decreased, while CXCR9 and interferon gamma increased. The distribution pattern of infiltrating monocytes/macrophages, visualized using a fluorescent perfluorocarbon emulsion, indicated that macrophages predominately localize in the vicinity of large blood vessels. Electron microscopy supports the presence of dense tumor cell masses throughout the tumor, with the largest vessels present in the surrounding mammary fat pad. Overall, large vessels in the 4T1 tumor periphery support high, localized vascular perfusion and myeloid accumulation. The pro-inflammatory cytokine IL-12 stimulated a transition towards T helper 1 cytokines in serum, supporting suppression of tumor growth and angiostatic conditions.