Background
Immunotherapy has revolutionized cancer treatment. However, most patients with advanced cancer do not respond to current immunotherapies or develop secondary resistance. Current regimens for cancer immunotherapy are mostly focused on using one type of immune cells called CD8 T cells. The Corthay lab (https://ous-research.no/corthay) has previously reported that another type of immune cells named macrophages may also be very efficient at fighting cancer. The main objective of this master project is to demonstrate in vitro the potential of macrophages for eliminating cancer cells.
In a tumor, the cancerous cells are surrounded by a tumor microenvironment typically consisting of extracellular matrix molecules, blood vessels, fibroblasts, and numerous types of immune cells. To mimic the tumor environment in 3D, we will take advantage of the tumor on chip technology.
Tumor on chip technology. (A) Example of a microfluidic device (tumor on chip). A complex tumor microenvironment is recreated in the tumor (red) chambers. (B) T-cell migration on chip. Tumor-specific CAR T cells (green) loaded in the immune chamber (left) are seen migrating towards the tumor chamber (right) via micro-channels (center). In the tumor chamber (right), a basic human tumor micro-environment was created in a 3D collagen gel. Upon migration CAR T cells make contacts with clusters of cancer cells (blue) and macrophages (white).
The master project
Time-lapse microscopy will be used to investigate the ability of mouse and human macrophages to eliminate cancer cells by cytotoxicity and phagocytosis. A critical R&D challenge is that the functions of macrophages in tumors are negatively influenced by the immunosuppressive tumor microenvironment. To solve this, we will optimize the activation of macrophages in vitro in a complex tumor microenvironment using microfluidic devices and 3D co-cultures (tumor on chip technology).
Specific aims of the master project
- To establish a microfluidic chip-based assay to visualize by time-lapse microscopy the killing of cancer cells by activated macrophages.
- To demonstrate the ability of mouse and human macrophages to kill cancer cells in a complex and immunosuppressive tumor microenvironment.
- To decipher the cellular and molecular mechanisms whereby macrophages kill cancer cells.