Humanized tumor mice–a new cutting-edge model to study immune responses in advanced cancer therapy

Introduction: Antibody-based cancer therapy (e.g Herceptin) represents a novel and promising therapeutic option for advanced oncologic disease. Nevertheless, due to lack of appropriate in-vivo models, the impact of the human immune system on antibody based cancer therapy still remains poorly understood. This constitutes a major issue in oncology that clearly requires further investigation.

Methods: For the generation of humanized tumor mice, NOD/scid/IL-2 receptor-γ chain-KO mice were irradiated (1Gy) and intrahepatically co-transplanted with 3×10⁶ Her2SK-BR-3 Her2+ human breast cancer cells and CD34+ stem cells purified from human umbilical cord blood by MACS sorting. For cell analyses, mononuclear cells were isolated from various (extra-) lymphoid organs and analyzed by polychromatic FACS using a FACScanto II flow cytometer.

Results: We found that humanized tumor mice (HTM) can be successfully generated by methods described above. Five weeks after intrahepatic transplantation, HTM developed a functional human immune system plus early disseminated tumor disease. Three months post transplantation, impressive macroscopic Her2+ liver tumors were detected. Tumor growth was accompanied by specific T cell maturation and activation including the induction of regulatory T cells and clonal T cell expansion. Importantly, we found increased numbers of activated NK cells in HTM, expansion and function of which could be further boosted by IL-15 treatment, demonstrating a possibility of immune cell modulation in antibody-based cancer therapy in vivo.

Conclusion: Our novel humanized tumor mice constitute a powerful in-vivo model that unprecedentedly empowers the investigation of human immune system-related cancer therapy, cancer therapy resistance, and underlying mechanisms.

Her2 - NK cells - antibody-based cancer therapy - hepatic cancer - humanized mice