Background:
A tumor consists not only of cancer cells, but of a wide range of cell types that influence both tumor progression and responses to therapy. These cells include immune cells, endothelial cells and fibroblasts. Cancer-associated fibroblasts (CAFs) are stromal cells that can make up a large part of a tumor, and that are generally found to be associated with a poor prognosis. CAFs have been shown to secrete factors that promote immunosuppression and cancer cell survival, and they are involved in resistance to various cancer treatments.
Radiotherapy is one of the most widely used treatment modalities for cancer. In recent years, radiation treatment combined with immune therapy has shown great potential to induce antitumor immunity and long-term responses in patients. Still, many do not respond to this treatment, and there is therefore a great need for more knowledge about how irradiation elicits anti-tumor immune responses, how these effects may be increased, and how treatment resistance may be overcome. Interestingly, it has recently been shown that using inhibitors of DNA damage repair can, in addition to radiosensitizing cancer cells, increase immune signaling after irradiation. However, CAFs are very radioresistant, and whether radiation combined with DNA repair inhibitors may be used to target CAFs and alter their immune signaling is not known.
The project:
The aim of this project is to investigate if treatment with radiation combined with inhibitors of the DNA damage response may be a strategy for targeting CAFs and making them switch from an immunosuppressive to an immune-stimulating phenotype. The student will use different assays to measure the immune signaling and cytokine release from CAFs derived from lung tumors, to see if the drugs of interest can promote immune activation after irradiation. Furthermore, the student will explore the signaling pathways involved, to elucidate the underlying mechanisms for immune signaling after the combination treatments. The results will increase our general understanding of how CAFs respond to radiotherapy, and potentially contribute to a new strategy for improving the outcome of radiation therapy and immune therapy for patients.
Methods:
We offer a great opportunity for a master student to learn how to plan, optimize and carry out experiments in a state-of-the-art laboratory. The student will learn how to use various methods to assess immune signaling in cells treated with irradiation and inhibitors of the DNA damage response. Among these methods are: cell culture techniques; DNA-damage induction by the use of an X-ray machine; multi-parameter flow cytometry, western blotting, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence microscopy to detect signaling events; metabolic assays to study cell viability.
Qualifications:
We seek a highly motivated and dedicated student with an interest in molecular cancer research.