Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice

Abstract

Humanized tumor mice (HTM) were generated by the co-transplantation of human hematopoietic stem cells and human breast cancer cells overexpressing HER2 into neonatal NOD-scid IL2Rγ(null) (NSG) mice. These mice are characterized by the development of a human immune system in combination with human breast cancer growth. Due to concurrent transplantation into newborn mice, transfer of MHC-mismatched tumor cells resulted in solid coexistence and immune cell activation (CD4(+) T cells, natural killer cells, and myeloid cells), but without evidence for rejection. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T and B cells allowing MHC-dependent interaction, and thereby the generation of T cell-dependent antibody production. Here, we investigated the capability of these mice to generate human tumor-specific antibodies and correlated immunoglobulin titers with tumor outgrowth. We found detectable IgM and also IgG amounts in the serum of HTM, which apparently controlled tumor development when IgG serum concentrations were above 10 µg/ml. Western blot analyses revealed that the tumor-specific antibodies generated in HTM did not recognize HER2/neu antigens, but different, possibly relevant antigens for breast cancer therapy. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g., humanization) for a potential application in humans. In addition, efficacy and safety of the generated antibodies can be tested in the same mouse model under human-like conditions. This might be of particular interest for cancer subtypes with no currently available antibody therapy.

Human cancer evolution in the context of a human immune system in mice

“…Previous studies in HSC‐transplanted NSG mice have reported primary tumor development, but with the exception of the study by Wang et al . (), the growth pattern was either not illustrated or largely heterogeneous (Rongvaux et al ., ; Schilbach et al ., ; Wege et al ., ). The apparent cancer tolerance in BRGS‐HIS mice was not only due to an overwhelming growth rate, since the slow‐growing MDA‐MB‐468 tumors were not rejected.…”

Humanized Mice as Unique Tools for Human-Specific Studies

“…MHC-mismatched tumor cells resulted in activated immune cells, but no clinical signs of rejection were observedWege et al (2014)CervicalHuman cervical carcinoma cell line (C33a) was subcutaneously engrafted into scid miceHerpes simplex virus type I-based oncolytic treatment in combination with radiation therapy may be an effective treatment for cervical cancerBlank et al (2002)Colorectal Rag2 −/− γc −/− mice were injected with human PBMCs and subcutaneously engrafted on the flank with colorectal carcinoma cell line (HT-29)Co-administration of Urelumab and Nivolumab slowed down tumor growth by elevating activated human T lymphocytes which produced IFN-γ and decreased levels of human regulatory T cells in tumor xenograftsSanmamed et al (2015)GastricPatient-derived xenografts of gastric cancer were subcutaneously engrafted into the right hind flank of scid and nude miceMice engrafted with patient-derived gastric cancers demonstrated identical histological and genetic diversities which corresponded to parental patient tumorsZhang et al (2015)HNSCCNSG mice were injected with expanded HSPCs and engrafted with patient-derived HNSCCHuman immune and stromal cells produced in XactMice mimics patient’s tumor microenvironment. This model was able to reverse genetic drift of tumors that usually occur after serial transplantation in non-humanized miceMorton et al (2016)KidneyNSG mice were engrafted with human RCC cell line (SKRC-59 cells) in the left subrenal capsule of their kidneyHuman anti-CAIX mAbs inhibit RCC growth by halting migration and triggering immune-mediated killing of RCC.…”

In vivomodels in breast cancer research: progress, challenges and future directions

“…One approach to achieve this is by incorporation of immune cells through co-transplantation of human CD34 + hematopoietic stem cells and breast cancer cells in immunodeficient mice (Wege et al, 2011, 2014). …”