Humanized mouse; A model for understanding tumor-immune system interactions
Ken-Edwin Aryee1, Michael A. Brehm1, Leonard D. Shultz1, 2 and Agata Jurczyk1
University of Massachusetts Medical School, Worcester, MA1;The Jackson Laboratory, Bar Harbor, ME, USA2
The kinetics of tumor growth and progression are governed by the interaction between tumor cells, the non-malignant stroma and immune cells of both innate and adoptive lineages. Studying tumor-immune system interactions has however been primarily restricted to mouse models, as studying of human immune system tumor interactions is limited logistically and ethically. Implanting of tumors into human immune system engrafted mice provides a way to probe the interactions between human immune cells and malignancies, and to test novel anti-tumor immunotherapies. We describe here, the use of the bone marrow/liver/thymus (BLT) humanized mouse model to study the interactions between the human immune system and PDX melanoma and response of the melanoma to immunotherapy modalities. The BLT mouse supports high levels of human immune system development including HLA-restricted T cells, B cells and innate immune cells. Using the NOD-scid IL2rnull (NSG) mice transgenically expressing SCF, GM-CSF and IL-3 (NSG-SGM3), we observed the infiltration of human leukocytes into the tumor microenviroment after implantation of patient-derived melanoma. Additionally, we recovered high levels of FoxP3+ regulatory T cells, tumor-associated macrophages and conventional CD4 and CD8 T cells expressing PD-1 and CTLA4 from the tumor, suggestive of an immune regulatory environment generated in the melanoma growing within mice similar to that seen in patients. Melanoma PDX in the NSG-SGM3 BLT mice responded to anti-PD-1 antibody (Keytruda) treatment with an increase in tumor infiltrating CD4+ and CD8+ T cells. These results suggest that tumors implanted into NSG-SGM3 BLT mice can be used as an effective model for understanding tumor-immune system interactions and for testing immune therapeutics.