Humanized mouse models for translational cancer research and immunotherapy
Humanized mice (immunodeficient mice reconstituted with a human immune system) represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. We have developed a humanized mouse model that supports growth of patient-derived tumor xenografts (PDX), autologous reconstitution with innate and adaptive human immune cells, and personalized cancer immunotherapy. Our humanized mouse model will allow us to investigate how the tumor microenvironment regulates human anti-tumor immune responses in vivo, which mechanisms promote immune cell exhaustion, tumor resistance and metastasis, and which combinations of cancer immunotherapies will be most successful in eliminating specific types of cancers.
Figure 1: Development and characterization of SRG-15 humanized mice. (A) Schematic representation of the targeted Sirpα allele with human exons 2-4 highlighted in blue. (B) Efficient engraftment of human hematopoietic cells in the blood of NSG, SRG and SRG-15 humanized mice 11-14 weeks post engraftment with human CD34+ cells. (C) ViSNE single marker 2D-scatter plots (from 33 parameter mass cytometry), showing the expression level (red = high; blue = low) of 7 markers in CD56dim CD16+ NK cells in SRG-15 humanized mice (n=9; spleen) and humans (n=20; blood).
Figure 2: Anti-SIRPα antibody immunotherapy enhances myeloid cell anti-tumor activity. (A) Overlay of the crystal structures of anti-SIRPα:SIRPα and CD47:SIRPα complexes. (B) Tumor volume and weight in SRG mice treated with PBS (n=8), rituximab (n=3), anti-SIRPα (KWAR23; n=4) or rituximab + anti-SIRPα (KWAR23; n=14). The color of the stars indicates comparison of the corresponding group to the rituximab + KWAR23 group.
Long noncoding RNA regulation of adaptive immunity
Long noncoding RNAs (lncRNAs) play a key role in regulating tumor growth and immune cell responses. By using deep RNA-seq we identified novel lncRNAs regulating adaptive immunity. By using CRISPR/Cas9-mediated genome engineering, we generated lncRNA knockout mice to understand how they regulate immune cell development and adaptive immunity.
Stromal regulation of immune cell development
Stromal cells maintain hematopoietic stem cells (HSC) and provide lineage-instructive differentiation signals to lymphoid progenitors. We have developed reporter and conditional knockout mice to investigate the role of distinct subsets of stromal cells for immune cell development and the regulation of immune cell responses.