Ruprecht-Karls-Universität Heidelberg
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Cerwenka0218 - Scientist (f/m) / PhD position
Project no:
Cerwenka0218

Project leader:

Project supervisor:
Cerwenka, Adelheid
Application deadline:
31. Jan 2019
Start of PhD project:
1. Mar 2019

Project description:

Title:
Exploring the tumor microenvironment to improve immunotherapy of cancer
Summary:
The immunotherapy of cancer has yielded remarkable success during the past years in the clinics. However, immune cells become dysfunctional in the tumor microenvironment and it is a major challenge in the field to unleash and re-activate their anti-tumor activity. Regulation of immune cell reactivity in cancer is incompletely understood and a better knowledge of the regulatory networks in the tumor microenvironment will lead to improved therapies.
Our laboratory has a long-standing expertise in the field of innate immunity in particular in studying the biology of Natural Killer cells. Since Natural Killer cells can kill cancer cells and produce inflammatory cytokines they are promising novel tools for cancer immunotherapy. Here, we will investigate whether Natural Killer cells and Innate lymphoid cells in general are influenced in their anti-tumor activity by non-immune cells such as different types of stroma cells in the liver tumor microenvironment. Our research questions will be addressed in mouse models and with cells from liver cancer patients.
In our laboratory, we have generated unique conditional knock-out mouse lines that lack transcription factors that are known to be activated by micro environmental cues in NK cells. These mouse lines show altered anti-tumor responses. Using state of the art RNAseq, ATA-Cseq, single cell sequencing, functional assays with NK cells from mouse liver cancer models and assays with cells of liver cancer patients, this project will uncover the importance of these transcription factors in NK cell responses in the tumor microenvironment.
The results obtained in our study will identify novel components in the tumor microenvironment as additional regulators of innate immunity in the liver, revealing innovative thera¬peutic strategies and targets for the treatment of liver disease.
References:
1. Cerwenka A, Lanier LL. Natural killers join the fight against cancer. Science. 2018 Mar 30;359(6383):1460-1461. doi: 10.1126/science.aat2184.

2. Stojanovic A, Cerwenka A. Checkpoint inhibition: NK cells enter the scene. Nature Immunol. 2018 Jun 18. doi: 10.1038/s41590-018-0142-y. [Epub ahead of print]

3. Correia MP, Stojanovic A, Bauer K, Juraeva D, Tykocinski LO, Lorenz HM, Brors B, Cerwenka A. Distinct human circulating NKp30+FcεRIγ+CD8+ T cell population exhibiting high natural killer-like antitumor potential. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5980-E5989. doi: 10.1073/pnas.1720564115. Epub 2018 Jun 12.

4. Pollmann J, Götz JJ, Rupp D, Strauss O, Granzin M, Grünvogel O, Mutz P, Kramer C, Lasitschka F, Lohmann V, Björkström NK, Thimme R, Bartenschlager R, Cerwenka A. Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis. J Hepatol, 68: 421-30, 2017.

5. Cerwenka A, Lanier LL, 2016, NK cell memory in viral infection, inflammation and cancer, Nature Immunology Reviews; Feb;16(2):112-23. doi: 10.1038/nri.2015.9. Epub 2016 Jan 25

6. Stojanovic A, Fiegler N, Brunner-Weinzierl M and Cerwenka A. CTLA-4 is expressed by activated mouse NK cells and inhibits NK cell IFN-g production in response to mature dendritic cells, J Immunol. 2014 May 1;192(9):4184-91
Methods that will be used:
Cell culture, flow cytometry, cell sorting, next generation sequencing, single cell sequencing, ATA-Cseq, different conditional mouse models of liver cancer, analysis of human immune cells from patients suffering from liver disease.
Cooperation partners:
The project is embedded into SFB 1366 network “Vaskular control of organ function” of the DFG. Retreats will take place to discuss results and to exchange reagents and protocols. PhD students will also have external mentors for discussion of results.
Personal qualifications:
We are searching for a highly motivated PhD candidate with strong interest in immunology and its fascinating complexity. The qualified candidate should have a master degree or equivalent degree in Cell Biology, Immunology or a related field. Research experience and excellent written and spoken English is a prerequisite. The candidate will work in a friendly and supportive environment and can participate in a broad range of career development, scientific and professional skill courses offered by the Graduate Program.
Keywords:
Immunology, liver sinusoidal endothelial cells, Innate Immunity, Liver disease, Innate Lymphoid Cells; Cancer