Detail

Keywords

Abelson murine leukemia virus; Cytokines; Immunotherapy; Leukemia; Receptors, Natural Killer Cell; Suppressor of Cytokine Signaling Proteins

Research group(s)

• Eva König
  Head: Emilio Casanova
  Research Area: tumor immunology, natural killer (NK) cells, immunoediting, tumor evolution, cytokines, JAK/STAT/SOCS signaling, leukemia, melanoma, cellular immunotherapy
  Members:
  Eva Maria König

Research interests

The principle of cancer immunoediting allows a deeper understanding of the dual action of immunity on cancer. Whereas the immune system can detect and destroy transformed cells, the constant immune pressure evokes sculpting of the tumor that eventually leads to immune escape. During cancer immunoediting, the host immune system shapes the tumor in three consecutive steps. (i) In the elimination phase, malignant cells are destroyed by a competent immune system. (ii) Tumor cells that manage to survive immune cell-mediated destruction enter an equilibrium phase characterized by sculpting and editing of individual cell clones. (iii) In the escape phase, the edited tumors, which are refractory to immune cell eradication, start to grow and become clinically apparent.

Natural killer (NK) cells are highly cytotoxic innate immune cells and the first line of defense against physiologically stressed cells such as tumor cells and virus-infected cells. In recent years, novel cancer immunotherapies have reached clinics and have shown promising results. In particular, the clinical application of NK and T cells against cancer is an area of extensive investigation. However, the lack of sustained therapeutic efficacy and the development of therapy resistance are still challenges we seek to overcome. 

Techniques, methods & infrastructure

We use a combination of single-cell tracking and next-generation sequencing of tumor cells to quantify the process of NK cell-mediated tumor immunoediting and uncover novel mechanisms of tumor escape. To quantitatively assess NK cell-mediated tumor immunoediting, we use DNA barcoding. The inheritable sequence of the DNA barcode, akin to commercial products, marks each individual B-ALL cell and allows the simultaneous tracking of individual tumor clones under various experimental conditions over extended periods of time. To functionally test various genes in NK cell-mediated anti-tumor immunity, we use gene-modified mice and a multitude of in vivo mouse tumor models as well as human NK cells isolated from the blood of healthy donors. Our in vitro assay repertoire includes multi-color flow cytometry, standard molecular biology and functional assays, cellular barcoding, primary cell transduction, gene knockdown and knockout, next-generation sequencing, mass spectrometry, etc.

Grants

• Non-canonical STAT1 signaling in natural killer cells (2021)
  Source of Funding: FWF (Austrian Science Fund), Stand-alone
  Principal Investigator
• Art 4 Science (2019)
  Source of Funding: FWF (Austrian Science Fund), Wissenschaftskommunikation
  Principal Investigator
• Find tumor immune evasion strategies by cellular barcoding (2018)
  Source of Funding: FWF (Austrian Science Fund), Stand-alone
  Principal Investigator
• NLRP1 and NLRP3 in T and NK cell immunity (2014)
  Source of Funding: FWF (Austrian Science Fund), Erwin Schrödinger
  Principal Investigator
• STAT1 Serine727 – Key Regulator for NK Cell-Mediated Cytotoxicity and Tumor Surveillance (2008)
  Source of Funding: OeAW (Austrian Academy of Sciences), DOC
  Principal Investigator

Selected publications

1. Yuan, D. et al. (2023) ‘NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages’, Proceedings of the National Academy of Sciences, 120(47). Available at: https://doi.org/10.1073/pnas.2302126120.
2. Gotthardt, D. et al. (2019) ‘JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation’, Frontiers in Immunology, 10. Available at: https://doi.org/10.3389/fimmu.2019.02590.
3. Putz, E.M. et al. (2017) ‘NK cell heparanase controls tumor invasion and immune surveillance’, Journal of Clinical Investigation, 127(7), pp. 2777–2788. Available at: https://doi.org/10.1172/jci92958.
4. Delconte, R.B. et al. (2016) ‘CIS is a potent checkpoint in NK cell–mediated tumor immunity’, Nature Immunology, 17(7), pp. 816–824. Available at: https://doi.org/10.1038/ni.3470.
5. Putz, E.M. et al. (2016) ‘Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity’, OncoImmunology, 5(9), p. e1186314. Available at: https://doi.org/10.1080/2162402x.2016.1186314.