Multimodal imaging of the tumor microenvironment and biological responses to immune therapy
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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-llo 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.
KeywordsTumor vasculature computed tomography Electron microscopy Interleukin 12 Magnetic resonance imaging
We wish to acknowledge use of the Animal Resource Facilities at the University of New Mexico, Houston Methodist and Baylor College of Medicine. Imaging equipment and tissue processing were provided by the UNM Animal Models and Microscopy Facilities and the Human Tissue Repository and Tissue Analysis Facility, supported by the UNM Cancer Center Support Grant NCI 2P30 CA118100-11, PI Willman, C. The UNM Center for Micro-Engineered Materials Electron Microscopy Facility provided the FEI Quanta 3D Dual Beam FIB-FEGSEM for tissue electron microscopy. We are grateful to the MD Anderson Cancer Center Small Animal Imaging Facility, the Houston Methodist PET-CT Facility, and Baylor College of Medicine Small Animal MRI Core for assistance with in vivo imaging studies.
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