Medical University of Vienna
Department of Medicine I
Institute for Cancer Research
1090 Vienna, Austria
Phone: +43 1 40160-57577
Fax: +43 1 40160-957526
Humanized mouse models for translational cancer research and precision medicine
Our laboratory is interested in understanding the tumor-immune microenvironment (TIME), immunotherapy resistance and tumor escape. We have developed a next-generation humanized mouse model that promotes the growth of a multitude of patient tumors and supports the development of a diverse and functional human adaptive and innate immune system. By integrating the complexity of the patient’s tumor and immune system in a novel in vivo model, we aim to advance precision immuno-oncology by providing a framework for effective combination treatment approaches for cancer patients.
Stromal regulation of immune cell development and anti-tumor immunity
Mesenchymal stromal cells maintain hematopoietic stem cells (HSC) and provide lineage-instructive differentiation signals for the development of a diverse immune system. We have developed reporter knock-in mice and conditional knock-out mice to investigate the role of distinct subsets of stromal cells for immune cell development and the regulation of immune cell responses, as seen in the tumor-stroma-immune microenvironment.
A novel humanized mouse model to investigate the tumor-immune microenvironment (TIME) and therapy resistance mechanisms
Cancer immunotherapy has provided significant clinical benefit to a number of patients with advanced disease. However, the need for more precise immunotherapies and predictive biomarkers remains of paramount importance, as complete and durable responses are only seen in 15-20% of patients. By integrating the complexity of the patient’s tumor and immune system in a novel in vivo model, we will be able to model the patient’s TIME in vivo and address whether/which checkpoint inhibitors and/or MDR-selective compounds have the potential to overcome therapy resistance mechanisms. To address this, we have developed a next-generation humanized mouse model called “MISTRG-6-15”, which supports the growth of patient-derived tumors and enables combination therapy screenings. In this research project we will (1) characterize tumor-infiltrating immune cell subsets in therapy-resistant patient cancers using single-cell sequencing and 13-color flow cytometry, (2) establish a collection of patient-derived tumor xenografts (PDX) and (3) investigate how checkpoint inhibitors and/or MDR-selective compounds remodel the TIME and affect therapy resistance and tumor escape in MISTRG-6-15 humanized mice. In summary, we will integrate the complexity of the patient’s tumor and immune system in a novel in vivo model, thereby aiming to advance precision immuno-oncology by uncovering novel therapeutic targets and prognostic markers and by providing a framework for effective combination treatment approaches for cancer patients.
- Herndler-Brandstetter D*, Ishigame H*, Shinnakasu R, Plajer V, Stecher C, Zhao J, Lietzenmayer M, Kroehling L, Takumi A, Kometani K, Inoue T, Kluger Y, Kaech SM, Kurosaki T, Okada T, Flavell RA. KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity. Immunity 48(4): 716-729, 2018. * contributed equally
- Herndler-Brandstetter D*, Shan L*, Yao Y, Stecher C, Plajer V, Lietzenmayer M, Zheng Y, Strowig T, de Zoete MR, Palm NW, Chen J, Blish CA, Gurer C, MacDonald LE, Murphy AJ, Valenzuela DM, Yancopoulos GD, Montgomery RR, Flavell RA. Humanized mouse model supports development, function, and tissue residency of human natural killer cells. PNAS 114(45): E9626-E9634, 2017.
- Guo Ring N*, Herndler-Brandstetter D*, Weiskopf K*, Shan L, Volkmer J, George BM, Lietzenmayer M, McKenna KM, Naik TJ, McCarthy A, Zheng Y, Ring AM, Flavell RA#, Weissman IL#. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage anti-tumor activity. PNAS 114(49): E10578-E10585, 2017.
- Cordeiro Gomes A*, Hara T*, Lim VY*, Herndler-Brandstetter D, Nevius E, Sugiyama T, Tani-ichi S, Schlenner S, Richie E, Rodewald HR, Flavell RA, Nagasawa T, Ikuta K, Pereira JP. Hematopoietic stem cell niches control multipotent progenitor differentiation. Immunity 45(6): 1219-1231, 2016.
- Herndler-Brandstetter D. How aging affects T lymphocyte-mediated immunity. Front Immunol 4: 296, 2013 (Editorial)
- Herndler-Brandstetter D, Landgraf K, Tzankov A, Jenewein B, Brunauer R, Laschober GT, Parson W, Kloss F, Gassner R, Lepperdinger G, Grubeck-Loebenstein B. The impact of aging on memory T cell phenotype and function in the human bone marrow. J Leuk Biol 91(2): 197-205, 2012.
- Herndler-Brandstetter D, Landgraf K, Jenewein B, Tzankov A, Brunauer R, Brunner S, Parson W, Kloss F, Gassner R, Lepperdinger G, Grubeck-Loebenstein B. Human bone marrow hosts polyfunctional memory CD4+ and CD8+ T cells with close contact to IL-15-producing cells. J Immunol 186(12): 6965-6971, 2011.