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 tumour that eventually leads to immune escape. During cancer immunoediting, the host immune system shapes the tumour in three consecutive steps. (i) In the elimination phase, malignant cells are destroyed by a competent immune system. (ii) Tumour 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 tumours, which are refractory to immune cell eradication, start to grow and become clinically apparent.
In recent years, novel anti-cancer therapies have reached clinics and shown promising results. In particular, the clinical application of NK and T cells against cancer is an area of extensive investigation. However, we are still facing challenges caused by resistance to therapy and secondary metastasis. The combination of single-cell tracking by DNA barcoding and next-generation sequencing will enable a deeper understanding of the mutational landscape of tumours. The identification of basic mechanisms underlying tumour immune escape is of utmost importance to find novel therapeutic targets that show sustained success.
We aim to…
- quantify the process of NK cell-mediated leukaemia immunoediting.
- identify the molecular signature of NK cell-resistant tumour cell clones.
- find novel therapeutic targets to increase the immunogenicity and susceptibility of tumour cells towards NK cell-mediated surveillance.
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 ]
Putz EM, Gotthardt D, Hoermann G, Csiszar A, Wirth S, Berger A, Straka E, Rigler D, Wallner B, Jamieson AM, Pickl WF, Zebedin-Brandl EM, Müller M, Decker T, Sexl V. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 2013 Aug 15;4(3):437-44. [ https://www.ncbi.nlm.nih.gov/pubmed/23933255 ]
Stand-Alone Project (P32001-B) funded by the Austrian Science Fund (2019-2021).