#Improving #immunotherapy #regulating #metabolism #dendritic #cells #cells
Cells of the immune system, and in particular dendritic cells (DCs) and T cells, play a crucial role in protection against cancer. Therefore, there is great interest in developing immunotherapies that improve the anti-tumor function of these cells. Like all cells, DCs and T cells need nutrients to function properly. But tumors often contain so few nutrients that DCs and T cells no longer work properly.
Research direction/proposed solution
We have found that due to this limited availability of nutrients in tumors, the protein AMPK becomes active in DCs and T cells, which we have found in experiments to inhibit the function of these cells. Counteracting AMPK activation in these cells in tumors therefore offers an interesting new opportunity to increase their anti-tumor activity.
Relevance
Current immunotherapies against cancer do not yet work optimally in many cases because DC and T cells are often inhibited in their function in tumors. It is therefore important to find out whether AMPK activation plays a role in this, so that we can counteract it and make immunotherapies more effective.
Research questions
In the current project we want to investigate the mechanism by which AMPK activation limits the function of DCs and T cells and determine whether AMPK inhibition in these cells in tumors has the potential to improve existing immunotherapies.
Research design
First we want to investigate what happens to the anti-tumor immune response when we remove AMPK from DCs and T cells, by using mice in which AMPK has been genetically deleted specifically in DCs or T cells. We next want to determine the mechanism by which AMPK activation leads to inhibition in DC and T cell function. We will investigate this in experiments with cultured DCs and T cells. In the third part of this project, we want to determine in an animal model whether inhibiting AMPK signaling in a therapeutic setting can improve anti-tumor immune responses in combination with other forms of immunotherapy. In addition, we will test whether inhibition of AMPK can improve the function of DCs and T cells derived from tumor tissue of skin and colon cancer patients.
Expected outcomes
The experiments described will identify how exactly AMPK activation affects DC and T cell function in tumors. In addition, we expect that inhibiting AMPK activation in DCs and T cells will lead to a greatly improved anti-tumor immune response, resulting in a better clinical course.
Steps required to implement results
In follow-up studies, it will first be necessary to test on a larger scale whether inhibition of AMPK activation can improve the function of DCs or T cells from different types of cancer patients and for how long AMPK inhibition has an effect before it can be tested in clinical studies. For clinical translation, the availability of clinically approved AMPK inhibitors is also a prerequisite, which is currently not the case. Our research will enable us to make this clinical translation.
