Reconstitution Of The Human Ovarian Tumor-Microenvironment In Cd34-Transplanted Nod-Scid-Il2r Gamma C Null (Nsg) Mice

The use of stem cell-derived human immune system NSG mice and orthotopic tumors to recapitulate the human ovarian tumor microenvironment represents a significant improvement over existing mouse models of cancer. However, the careful phenotyping of a human ovarian tumor microenvironment in NSG mice has not been reported. We characterized the human ovarian tumor microenvironment in NSG mice reconstituted with a full human immune system using cord blood-derived CD34+ cell transplantation, and injected with human ovarian tumor cells. Our findings demonstrated human B cell and T cell infiltration in both orthotopic and subcutaneous tumors. Orthotopic tumors showed a 3 to 4-fold increase of human CD3+ cell infiltration in comparison with subcutaneous tumors or spleens from tumor bearing mice, however, the overall CD4/CD8 T cell ratio was similar in both tumor sites. Tumor-infiltrating T cells included effector memory TEM cells and Treg cells. Orthotopic tumor dissociates also contained significantly more human macrophages (TAMs) than subcutaneous tumors or spleens from tumor bearing mice. While all macrophages were found to have an M1-like phenotype, TAM subsets could be distinguished from splenic macrophages by CD40 or HLA-DR expression and TNFβ secretion. Furthermore, TAMs phenotypic differences observed in orthotopic tumors were associated with faster tumor growth kinetics and metastasis. Finally, we found that, in addition to the murine origin of the tumor stroma, a significant number of mouse neutrophils and macrophages were also present. We propose that humanized mice bearing human tumors could be a valuable tool for the preclinical evaluation of targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-286. doi:10.1158/1538-7445.AM2011-LB-286