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.
Challenges in immunotherapy
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.
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. The identification of the molecular signature of NK cell-resistant tumor cell clones will provide the basis for the discovery of novel therapeutic targets to increase the immunogenicity of tumor cells. Alternatively, we aim to increase the cytotoxic function of NK cells. Previously, we have shown that in addition to mediating cytokine responses via the canonical JAK/STAT pathway, STAT1 participates in non-canonical signaling pathways in NK cells initiated at the immunological synapse formed upon target cell contact. From our previous studies, we learned that STAT1-S727 phosphorylation reduces NK cell cytotoxicity, thereby representing an interesting target to improve NK cell functionality for the use in immunotherapies.
We aim to define the signals and the upstream kinase(s) responsible for non-canonical STAT1 activation upon target cell contact and to study the general role of these kinase(s) in NK cells.
NK cell research essential for new therapy
We believe that a better understanding of the tumor evasion mechanisms and of the molecular pathways activated in NK cells upon the recognition of tumor cells are of the utmost importance to find novel therapeutic targets.
Projects and Funding
- Non-canonical STAT1 signaling in natural killer cells
CCRI responsible Principal Investigator: Eva König
Grant from the Austrian Science Fund (FWF), Stand-Alone project, ID – P 34832
Duration: 01/01/2022 to 31/12/2025
Find tumor immune evasion strategies by cellular barcoding
CCRI responsible Principal Investigator: Eva König
Grant from the Austrian Science Fund (FWF), Stand-Alone Project, ID – P 32001
Duration: 15/03/2019 to 14/09/2023
How do leukemic cells escape natural killer cell-mediated surveillance?
CCRI responsible researcher: Michelle Buri (supervisor: Eva König)
Grant from the Austria Academy of Sciences (ÖAW), DOC fellowship ID – 25905
Duration: 01/08/2021 to 01/08/2024
Gotthardt D, Trifinopoulos J, Sexl V, Putz EM. JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation. Front Immunol. 2019 Nov 12;10:2590. doi: 10.3389/fimmu.2019.02590. eCollection 2019 [https://www.ncbi.nlm.nih.gov/pubmed/31781102]
Nakamura K, Kassem S, Cleynen A, Chrétien ML, Guillerey C, Putz EM, Bald T, Förster I, Vuckovic S, Hill GR, Masters SL, Chesi M, Bergsagel PL, Avet-Loiseau H, Martinet L, Smyth MJ. Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer Cell. 2018 Apr 9;33(4):634-648.e5. [ https://www.ncbi.nlm.nih.gov/pubmed/29551594 ]
Putz EM, Mayfosh AJ, Kos K, Barkauskas DS, Nakamura K, Town L, Goodall KJ, Yee DY, Poon IK, Baschuk N, Souza-Fonseca-Guimaraes F, Hulett MD, Smyth MJ. NK cell heparanase controls tumor invasion and immune surveillance. J Clin Invest. 2017 Jun 30;127(7):2777-2788. [ https://www.ncbi.nlm.nih.gov/pubmed/28581441 ]
Putz EM, Majoros A, Gotthardt D, Prchal-Murphy M, Zebedin-Brandl EM, Fux DA, Schlattl A, Schreiber RD, Carotta S, Müller M, Gerner C, Decker T, Sexl V. Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity. Oncoimmunology. 2016 May 19;5(9):e1186314. [ https://www.ncbi.nlm.nih.gov/pubmed/27757297 ]
Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NP, Linossi EM, Burns CJ, Carotta S, Gray DH, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol. 2016 Jul;17(7):816-24. [ https://www.ncbi.nlm.nih.gov/pubmed/27213690 ]
National: Dagmar Gotthardt and Veronika Sexl (University of Veterinary Medicine Vienna), André Müller and Christoph Bock (CeMM, Vienna), Emilio Casanova, Thorsten Füreder, Gernot Schabbauer and Eva Zebedin-Brandl (Medical University of Vienna), Agnieszka Witalisz-Siepracka and Dagmar Stoiber-Sakaguchi (Karl Landsteiner University of Health Sciences, Krems) International: Tobias Bald (University of Bonn, Germany), Ton Schumacher (Netherlands Cancer Institute, Netherlands), Leïla Perié (Institut Curie, France), Fengyuan Tang (University of Basel, Switzerland), Francis Luca (University of Pennsylvania, USA), Juming Yan (Xuzhou Medical University, China)
About Eva König
Dr. Eva Maria König (PhD), graduating from the University of Vienna as a trained chemist in 2007, König (neé Putz) has worked in the field of tumor immunology, starting as a PhD student in the laboratory of Veronika Sexl (MUW and VetMed Uni Vienna) and proceeding as a postdoctoral fellow at the QIMR Berghofer Institute of Medical Research in Brisbane (Australia) and the Max Perutz Laboratories (Austria). In 2019, she established the Tumor Immunoediting group at the St. Anna Children’s Cancer Research Institute GmbH (CCRI) and together with her team of PhD and Master students and technical assistants, she aims to find novel targets to increase the susceptibility of tumor cells towards NK cell-mediated surveillance and/or to enhance NK cell functionality per se.