Ruprecht-Karls-Universität Heidelberg
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Cerwenka0118 - Scientist (f/m) / PhD position
Project no:
Cerwenka0118

Project leader:

Project supervisor:
Cerwenka, Adelheid
Application deadline:
15. Jul 2018
Start of PhD project:
1. Aug 2018

Project description:

Title:
Defining innate immune checkpoints controlling Natural Killer cell recognition of melanoma cells
Summary:
The immunotherapy of cancer such as the checkpoint inhibition of T cells has revolutionized cancer therapies and has improved the clinical outcome of a subset of cancer patients. A substantial fraction of patients, however, does not respond or develops resistance to these targeted therapies. These resistant tumors, however, can be efficiently recognized and attacked by the innate immune system. Natural killer (NK) cells are innate immune effector cells that can provoke potent anti-tumor activity when appropriately activated in the tumor microenvironment. Their activation is counterbalanced by inhibitory clues from cancer cells or regulatory immune cells. So far, the impact of inhibitory pathways on tumor cell-induced NK cell activation is still incompletely understood. Also, the nature of NK cell inhibitory receptors and checkpoint molecules has remained rather elusive. Our group has a long-standing expertise in the cytotoxic potential of NK cells towards cancer cells, the interaction of NK cells with adaptive and innate immune cells, the functionality of NK cell activating receptors like NKG2D, NKp30 and CD16, and the discovery of novel ligands for NK cell activating and inhibiting receptors.
In this project, the PhD candidate will set-up sophisticated cell biology and molecular biology-based tools and assays to investigate NK cell receptor pathways in response to melanoma cells. The PhD candidate will develop an immune-oncology CRISPR/Cas9-based screening approach with primary NK cells, NK cell lines and melanoma cells. The contribution and function of identified target molecules in the interaction of NK cells with melanoma cells will be examined, and ultimately, relevant target molecules may reveal novel candidates for immunotherapeutic interventions.
References:
Cerwenka A, Lanier LL: Natural killers join the fight against cancer. Science. 2018 Mar 30;359(6383):1460-1461. doi: 10.1126/science.aat2184. No abstract available.

Pahl JHW, Koch J, Gotz JJ, Arnold A, Reusch U, Gantke T, Rajkovic E, Treder MS, Cerwenka A. CD16A activation of NK cells promotes NK cell proliferation and memory-like cytotoxicity against cancer cells. Cancer Immunology Research, 2018, epub ahead of print

Ewen EM, Pahl JHW, Miller M, Watzl C, Cerwenka A. KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells. European Journal of Immunology, 2018, 48(2):355-365

Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Nature Reviews Immunologoy, 2016, 16(2):112-123

Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, Heckl D, Ebert BL, Root DE, Doench JG, Zhang F. Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells. Science, 2014, 3;343(6166):84-87

Khandelwal N, Breinig M, Speck T, Michels T, Kreutzer C, Sorrentino A, Sharma AK, Umansky L, Conrad H, Poschke I, Offringa R, König R, Bernhard H, Machlenkin A, Boutros M, Beckhove P. A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes. EMBO Molecular Medicine, 2015, 7(4):450-63
Methods that will be used:
In vitro cell culture-based methods, flow cytometry, cell sorting, transfections and transductions, CRISPR/Cas9-based methods, and next generation sequencing.
Cooperation partners:
This project will be performed in close collaboration with the Boutros group German Cancer Research Center (DKFZ). The project is part of a DFG-research training group (RTG) “Hallmarks of skin cancer” that provides talented and ambitious candidates with an excellent and stimulating research environment. The RTG will closely collaborate with the existing Life Science Graduate Schools of Heidelberg University and the DKFZ to provide excellent teaching in basic molecular and cellular biology, as well as in general cancer biology and oncology. Research will be jointly conducted by principle investigators based in Heidelberg/Mannheim and London collaborators.
Further information about the RTG can be found at the website: http://www.rtg2099.de/
Personal qualifications:
The successful candidate must hold a university degree (master or equivalent above average) that permits access to undertake doctoral studies. The candidate
is expected to demonstrate in-depth knowledge in cellular and molecular biology and/or immunology. Hands-on experience in molecular genetics and CRISPR/Cas9 technology is a plus. Moreover, very good English skills (spoken and written) are mandatory. The candidate should be driven by self-motivation, should share a vivid passion for scientific problems and should acknowledge interdisciplinary collaborative research in order to successfully master this doctoral study program.
Keywords:
Innate Immunity, immunotherapy, checkpoint inhibition, NK cells, CRISPR/Cas9