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Research Projects

Herndler-Brandstetter Lab
  1. Center for Cancer Research
  2. Research Focuses
  3. Cellular and Molecular Tumor Biology
  4. Dietmar Herndler-Brandstetter
  5. Research Projects

Humanized mouse models for translational cancer research and immunotherapy

Humanized mice (immunodeficient mice reconstituted with a human immune system) represent a promising tool for precision medicine as they may allow modeling and therapy of human diseases in vivo. We use a humanized mouse model that supports the development of a functional human immune system, the growth of patient-derived colorectal cancers, and 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 combination therapies will be most successful in eliminating specific types of colorectal cancer.

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.