Find tumor immune evasion strategies by cellular barcoding
Find tumor immune evasion strategies by cellular barcoding
Disciplines
Computer Sciences (10%); Clinical Medicine (40%); Medical-Theoretical Sciences, Pharmacy (50%)
Keywords
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Tumor Immunoediting,
Natural Killer Cells,
Cellular Barcoding,
Mechanisms Of Tumor Escape,
Leukemia
Cancer is a leading cause of death worldwide, accounting for 8.8 million deaths in 2015. One of the most recent and highly successful advances in anti-cancer treatment is cancer immunotherapy. As cancer patients are frequently suffering from immunosuppression, immunotherapy aims at re-activating the immune system. Natural killer (NK) cells are at the forefront of the bodys anti-tumor defense capable to directly kill tumor cells and to activate other immune cells. Novel therapies including the infusion of pre-activated NK cells into tumor patients have shown extraordinary performance. However, certain limitations curtail the success story. Malignant cells are highly adaptable to their environment and capable to efficiently evade from immune surveillance. The concept of immunoediting describes the phenomenon that tumors change their appearance and become immune-resistant upon constant pressure imposed by the immune system. This concept has been shown in experimental models such as chemically-induced tumors, but whether and how it applies in other malignancies is still a matter of debate. In the present project we hypothesize that immunoediting takes place in natural tumors. There is unequivocal evidence for the importance of NK cells in the fight against leukemia. We thus choose leukemia as a model system to address whether NK cell-mediated immunoediting is taking place. The design of our study will allow two potential scenarios to be distinguished: (i) NK cells are able to kill most tumor cell clones but spare the few pre-existing resistant sub- clones (clonal selection) or (ii) NK cells shape tumors by classical immunoediting. We further aim to determine the underlying molecular mechanisms for tumor evasion from NK cell- mediated eradication. This is made possible by using a cellular barcoding system that allows tracking of single leukemic cells in mice. The combination of cellular barcoding and next generation sequencing enables us to determine changes causing immune-resistance and tumor outgrowth. A better understanding of the molecular mechanisms underlying tumor immune evasion is the first step to utilize the full potential of NK cells in anti-tumor therapy. Ultimately, this study will pave the way for new therapeutic approaches to treat tumors that have successfully evaded the immune system.
The term tumor immunoediting describes the dual role by which the immune system can suppress and promote tumor growth and is divided into three phases: elimination, equilibrium and escape. It elucidates the phenomenon whereby constant pressure exerted by the immune system can prompt tumors to alter their appearance to become resistant to immune cells. Natural Killer (NK) cells are part of the innate immune response and are primarily responsible for eliminating virus-infected and transformed tumor cells. In this project, we hypothesized that NK cells play a crucial role not only during the elimination phase but in all three stages of tumor immunoediting. To address this question, we developed an in vitro model in which murine BCR/ABLp185+ acute lymphoblastic leukemia (B-ALL) cells were co-cultivated with NK cells over an extended period. To quantitatively assess NK cell-mediated tumor immunoediting, newly generated B-ALL cell lines were labeled with DNA barcodes. 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. Our results demonstrated that the majority of tumor cell clones were efficiently eliminated by NK cells, with only a small fraction exhibiting intrinsic (primary) resistance to NK cells. Additionally, the application of DNA barcoding allowed us to prove the existence of tumor cell clones with secondary resistance, which developed resistance against NK cells during the course of co-culture. We found that the production of interferon- (IFN-) rather than direct cytotoxicity by NK cells, led to the emergence of highly resistant tumor cells. Besides well-known regulators of immune evasion, such as increased MHC-I expression, our detailed transcriptomic analysis of NK-resistant tumor cells revealed the upregulation of novel genes, such as lymphocyte antigen 6A (Ly6a), which, according to our functional tests, promoted NK cell resistance in leukemic cells. Our results underscore that during the equilibrium phase, tumor cells are actively edited by NK cells, employing various strategies to evade NK cell-mediated elimination.
- Shalin Naik, The University of Melbourne - Australia
- Ton N Schumacher, The Netherlands Cancer Institute - Netherlands
Research Output
- 67 Citations
- 9 Publications
- 2 Artistic Creations
- 5 Datasets & models
- 7 Disseminations
- 8 Scientific Awards
- 4 Fundings
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2024
Title A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations DOI 10.1038/s41467-024-47945-7 Type Journal Article Author Saldana-Guerrero I Journal Nature Communications Pages 3745 Link Publication -
2023
Title NK cells shape the clonal evolution of B cell leukaemia by IFN-? production DOI 10.1101/2023.11.16.567430 Type Preprint Author Buri M Pages 2023.11.16.567430 Link Publication -
2023
Title NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages DOI 10.1073/pnas.2302126120 Type Journal Article Author Yuan D Journal Proceedings of the National Academy of Sciences Link Publication -
2021
Title Pembrolizumab plus docetaxel for the treatment of recurrent/metastatic head and neck cancer: A prospective phase I/II study DOI 10.1016/j.oraloncology.2021.105634 Type Journal Article Author Fuereder T Journal Oral Oncology Pages 105634 Link Publication -
2022
Title High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma DOI 10.1016/j.canlet.2022.216028 Type Journal Article Author Grissenberger S Journal Cancer Letters Pages 216028 Link Publication -
2022
Title A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations DOI 10.1101/2022.11.21.515753 Type Preprint Author Saldana-Guerrero I Pages 2022.11.21.515753 Link Publication -
2022
Title High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma DOI 10.5167/uzh-226851 Type Other Author Grissenberger -
2019
Title JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation. DOI 10.3389/fimmu.2019.02590 Type Journal Article Author Gotthardt D Journal Frontiers in immunology Pages 2590 -
2020
Title Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function DOI 10.1038/s41467-020-17970-3 Type Journal Article Author Salzer B Journal Nature Communications Pages 4166 Link Publication
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2022
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Title Fashion design collection volume 2 by fashion designer Romana Zöchling (Label Ferrari Zöchling) Type Artwork Link Link -
2020
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Title Art4Science Songs and music videos "Hello", "Cellular Barcoding", "Labtalk" and "Heartbeat" by musician and composer Franz Reisecker Type Composition/Score Link Link
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2023
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Title Transcriptome of NK cell-resistant B-ALL cells DOI 10.1101/2023.11.16.567430 Type Database/Collection of data Public Access Link Link -
2023
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Title Chromatin accessability profile of NK cell-resistant B-ALL cells DOI 10.1101/2023.11.16.567430 Type Database/Collection of data Public Access Link Link -
2023
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Title RNA sequencing data from WT and NMDAR KO BMDMs, single-cell RNA sequencing data from tumors DOI 10.6084/m9.figshare.24447394 Type Database/Collection of data Public Access Link Link -
2023
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Title Expression analysis of anti- and pro-apoptotic genes across Ewing sarcoma samples DOI 10.1016/j.canlet.2022.216028 Type Database/Collection of data Public Access Link Link -
2022
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Title Neuroblastoma RNA and ATAC seq data DOI 10.1101/2022.11.21.515753v2 Type Database/Collection of data Public Access Link Link
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2023
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Title Long Night of Children's Cancer Research 2023 Type Participation in an activity, workshop or similar Link Link -
2020
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Title Art4Science Website Type Engagement focused website, blog or social media channel Link Link -
2020
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Title Art4Science radio show and podcasts Type A broadcast e.g. TV/radio/film/podcast (other than news/press) Link Link -
2022
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Title Long Night of Research 2022 Type Participation in an activity, workshop or similar Link Link -
2020
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Title Art4Science Knowledge Huddle with the GRASP Network Type Participation in an activity, workshop or similar Link Link -
2020
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Title Art4Science Social Media Channels Type Engagement focused website, blog or social media channel Link Link -
2019
Title Long Night of Research 2019 Type Participation in an activity, workshop or similar
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2023
Title Invitation as speaker at the Ri.MED research seminar series 2023 in Palermo, Italy Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International -
2023
Title Poster prize award at CCC-Trio symposium, Vienna, Austria Type Poster/abstract prize Level of Recognition Continental/International -
2023
Title EFIS EJI Travel Grant to visit the ENII Summer School, Italy, Alghero Type Poster/abstract prize Level of Recognition Continental/International -
2023
Title Mentorship of Dr. Charlotte Zajc (ESPRIT) Type Prestigious/honorary/advisory position to an external body Level of Recognition Regional (any country) -
2022
Title ÖGAI Travel grant to visit the Joint DGfI & ÖGAI Conference, Germany, Hannover Type Poster/abstract prize Level of Recognition Continental/International -
2022
Title Best oral presentation award at the 14th ÖGMBT Annual Meeting, Vienna, Austria Type Poster/abstract prize Level of Recognition National (any country) -
2022
Title Heribert-Konzett Prize of the Austrian Pharmacology Society (APHAR) Type Research prize Level of Recognition National (any country) -
2022
Title Invitation as Guest Editor in Frontiers in Immunology Type Appointed as the editor/advisor to a journal or book series Level of Recognition Continental/International
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2021
Title Fellinger Krebsforschung Type Research grant (including intramural programme) Start of Funding 2021 Funder Fellinger Krebsforschung -
2021
Title DOC [Doctoral Fellowship Programme of the Austrian Academy of Sciences] Type Fellowship Start of Funding 2021 Funder Austrian Academy of Sciences -
2022
Title Non-canonical STAT1 signaling in natural killer cells Type Research grant (including intramural programme) Start of Funding 2022 Funder Austrian Science Fund (FWF) -
2020
Title Art 4 Science Type Other Start of Funding 2020 Funder Austrian Science Fund (FWF)