Abstract
BackgroundOvarian cancer is immunogenic and residual tumor volume after surgery is known to be prognostic. Ovarian cancer often follows a recurring-remitting course and microscopic disease states may present ideal opportunities for immune therapies. We sought to establish the immune profile of a murine model of ovarian cancer that allows in vivo tumor imaging and the quantitation of microscopic disease.Results and DiscussionBaseline imaging and weight measurements were taken within 1 and 2 weeks after intraperitoneal tumor injection, respectively. Significantly higher photons per second from baseline imaging were first observed 5 weeks after tumor cell injection (p < 0.05) and continued to be significant through 8 weeks after injection (p < 0.01), whereas a significant increase in weight above baseline was not observed until day 56 (p < 0.0001). Expression of luc2 in ID8 cells did not alter the cellular immune microenvironment of the tumor. FOXP3+ T cells were more likely to be detected in the intraepithelial compartment and CD4+ T cells in the stroma as compared to CD3+ T cells, which were found equally in stroma and intraepithelial compartments.ConclusionsUse of an intraperitoneal tumor expressing a codon-optimized firefly luciferase in an immunocompetent mouse model allows tumor quantitation in vivo and detection of microscopic tumor burdens. Expression of this foreign protein does not significantly effect tumor engraftment or the immune microenvironment of the ID8 cells in vivo and may allow novel immunotherapies to be assessed in a murine model for their translational potential to ovarian cancers in remission or minimal disease after primary cytoreductive surgery or chemotherapy.MethodsMouse ovarian surface epithelial cells from C57BL6 mice transformed after serial passage in vitro were transduced with a lentiviral vector expressing a codon optimized firefly luciferase (luc2). Cell lines were selected and luc2 expression functionally confirmed in vitro. Cell lines were intraperitoneally (IP) implanted in albino C57BL/6/BrdCrHsd-Tyrc mice and albino B6(Cg)-Tyrc-2 J/J mice for serial imaging. D-luciferin substrate was injected IP and tumors were serially imaged in vivo using a Xenogen IVIS. Tumor take, weights, and luminescent intensities were measured. Immunohistochemistry was performed on tumors and assessed for immune infiltrates in stromal and intraepithelial compartments.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0060-6) contains supplementary material, which is available to authorized users.
Highlights
Ovarian cancer is immunogenic and residual tumor volume after surgery is known to be prognostic
Use of an intraperitoneal tumor expressing a codon-optimized firefly luciferase in an immunocompetent mouse model allows tumor quantitation in vivo and detection of microscopic tumor burdens. Expression of this foreign protein does not significantly effect tumor engraftment or the immune microenvironment of the ID8 cells in vivo and may allow novel immunotherapies to be assessed in a murine model for their translational potential to ovarian cancers in remission or minimal disease after primary cytoreductive surgery or chemotherapy
In order to determine if a lower number of implanted tumor cells could still be detectable by bioluminescence and still have a high engraftment rate, we injected mice with IP tumors of the ID8 cells with high expression of luc2 at both the reported number used in the parental line, 5×106 and 1×106 cells. 81% of mice injected with 1×106 cells had detectable tumor by 2 weeks after implantation
Summary
Ovarian cancer is immunogenic and residual tumor volume after surgery is known to be prognostic. We sought to establish the immune profile of a murine model of ovarian cancer that allows in vivo tumor imaging and the quantitation of microscopic disease. The ability of the immune system to recognize and respond to ovarian cancers has been known to be important in prognosis [1,2]. Mouse models for ovarian cancer may have more success in translational oncology if they can replicate the immune microenvironment and allow quantitation of low tumor volumes, two factors that are known to impact outcomes in human disease. Tumor volume continues to be an important factor in prognosis, where patients who achieve microscopic residual have a 34 months median overall survival advantage over those who have even 0.1 cm macroscopic disease after cytoreductive surgery [9]
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