Background:
Immune check-point inhibitors (ICI), a type of immunotherapy that activates a type of immune cells called T cells, show effects in many cancer patients. This demonstrates that immunotherapy has great potential in cancer treatment. Unfortunately, most patients with advanced cancer respond poorly to ICI, so there is a strong need for novel strategies for cancer immunotherapy.
A major focus in our research group is to activate another type of immune cells called macrophages to kill cancer cells in a direct or indirect manner through recruitment of T cells. We are also working on approaches that can stimulate antigen-presenting cells to induce strong T cell responses that can kill cancer cells. Recently, we found that human lung tumors contained more CD4+ Th2 cells than CD4+ Th1 cells, indicating a wrong type of ongoing immune response in human tumors. Effective anti-cancer immunity is believed to be mediated by CD4+ Th1 and CD8+ T cells corresponding to type 1 immunity. Thus, our goal is to develop treatment strategies that generate type 1 immunity in the tumor based on activation of macrophages and T cells.
In a tumor, the cancerous cells are surrounded by a tumor microenvironment typically consisting of extracellular matrix molecules, blood vessels, fibroblasts, and immune cells. To mimic the tumor environment in 3D, we will take advantage of the tumor on-a-chip technology. The tumor on-a-chip technology will in the master project be used to identify molecular compounds that can activate the tumor to recruit Th1 CD4+ T cells and CD8+ T cells.
The master project:
The microfluidic chip that will be used contains multiple chambers including a tumor chamber where cancer cells are seeded in a matrix to mimic the tumor microenvironment in 3D (Figure 1). The chips are produced by a collaborator and can be tailor-made for our purpose. The various cell types are labeled with different fluorescent dyes, and immune cell migration is analyzed by microscopy techniques and computer algorithms. We are currently establishing the tumor on-a-chip suitable for studies of migration, and the master student will work together with a researcher to establish the assay.
When the assay is established, the student will test different conditions and compounds for their ability to induce CD4+ Th1 and CD8+ T cell migration into the tumor/ tumor chamber. We have identified several combinations of compounds that can activate macrophages to either kill cancer cells or inhibit cancer cell growth and induce cytokines pivotal for type 1 immunity. These combinations of compounds will be tested in the migration assay. A selection of compounds that are successful in the migration assay will also be tested in mouse models of cancer to investigate whether they have potential to mediate inhibition of tumor growth and tumor rejection.
Specific aims of the master project:
- Establish the microfluidic chip-based migration assay in collaboration with a researcher.
- Test different conditions and compounds for their ability to induce CD4+ Th1 cell migration into the tumor/tumor chamber of the chip.
- Test different conditions and compounds for their ability to induce CD8+ T cell migration into the tumor chamber.
Importance/impact of the project:
- The assays will in the future be utilized in several projects.
- To identify conditions that lead to active recruitment of T cells into the tumor is considered one pivotal step in the development of successful immunotherapy.
Methods and tools that will be used in the master project:
- Isolation of cells from tissue, and culturing of cell lines and primary cells
- Labeling of cells with various fluorescent probes
- Tumor on-a-chip technology in close collaboration with the Hybrid Technology Hub, A centre of excellence (https://www.med.uio.no/hth/english/)
- Fluorescence microscopy techniques
- Image analysis by use of computer algorithms
- If time, test selected compounds which were successful in the chip, in a mouse model of cancer
About us:
The master project will be performed in the Tumor Immunology Lab (https://www.ous-research.no/corthay) under the supervision of Inger ?ynebr?ten (main supervisor) and Alexandre Corthay (co-supervisor). Finn-Eirik Johansen will serve as internal supervisor from IBV. The research focus of the group is tumor immunology and in particular, how antigen-presenting cells and T cells can be activated to fight cancer. In the group, we use standard molecular biology techniques, perform immunostaining of mouse and human cells and tissue, do flow cytometry, ELISA, multiplex analysis of cytokines, and microscopy. We use mouse models of cancer to test if strategies and compounds have potential in vivo. We are actively collaborating with other research groups in Oslo and abroad. As a member of our research group, you will be involved in weekly scientific meetings and journal clubs, and there will be several possibilities to present your project at meetings.