Prof. Linde Meyaard PhD and Michiel van der Vlist PhD (Center for Translational Immunology, UMC Utrecht and Oncode Institute for cancer research), in collaboration with Kristina Ganzinger PhD (AMOLF, Amsterdam), have received a NWO ENW-M2 grant of € 740,100. With help of this grant, two PhD students (one of each applicant) will collaborate to elucidate how inhibitory receptors initiate and relay their signals to dampen activation.

Our immune system needs to respond to and remove potential threats to our body, such as viruses, bacteria and malignant cells. To regulate these processes and prevent uncontrolled inflammatory responses that could damage healthy tissue, immune cells are equipped with an array of inhibitory receptors. The most compelling evidence for the power of these receptors comes from blocking them in people with cancer: blockade not only results in stronger anti-tumor responses but also in – potentially severe - side effects which resemble inflammatory disease.

Inhibition of stimulatory signals

The current understanding of how these receptors fine-tune the activation of immune cells is based on models of cell-cell interaction: the signal recognized by the inhibitory receptor is present on the opposing cell and the stimulatory signal affected by the inhibitory signal is in close proximity to the inhibitory receptor. “However”, says immunologist Michiel van der Vlist (Center for Translational Immunology, UMC Utrecht and researcher at Oncode Institute), “in many circumstances inhibitory receptors do not function within these restrictions and thus these models fail to explain their mode of action, representing a major knowledge gap in this field. Therefore, we will study (1) how inhibitory receptors that recognize soluble ligands are induced to signal and (2) how inhibitory receptors inhibit distal stimulatory signals.”

Experimental approach

Prof. Linde Meyaard (also Center for Translational Immunology, UMC Utrecht and investigator at Oncode Institute) explains the details of this research project: “Our preliminary work supports a hypothetical model in which the organization of inhibitory receptors and associated molecules in the cell membrane, both in space and time, defines signaling outcomes. To test this hypothesis, we need an experimental approach that can visualize where and when the stimulatory and inhibitory signals are given to cells and how this relates to functional outcome. Therefore, we teamed up with Kristina Ganzinger at AMOLF to use high resolution single-molecule microscopy to complement our functional and quantitative signaling assays. We will thus visualize and quantify the interactions of the individual signaling components in the membranes of live immune cells using single-molecule microscopy and connect this to functional outcomes at the cellular level using molecular and cellular read-outs.”

Collaboration

In this project, which will run for 4 years, UMC Utrecht will partner with physicist Kristina Ganzinger PhD (Autonomous Matter Department, AMOLF), an Amsterdam-based NWO institute for fundamental physics of complex matter with high societal relevance. One PhD candidate from UMC Utrecht (with a molecular or cellular immunology background) and one PhD candidate from AMOLF (with a biophysics background) will collaborate to find out how inhibitory receptors initiate and relay their signals to dampen activation. The outcome is expected to lead to a better understanding of the molecular mechanism of the induction, localization and effectuation of inhibitory receptor signaling, which will aid further research into the design of molecules to therapeutically target this class of receptors.

“Our overall aim is to unravel the molecular arrangement of signaling inhibitory immune receptors in the cell membrane, which is still largely a black box. This knowledge will be instrumental in developing therapeutics that target such receptors in cancer and inflammation,” concludes Linde.

NWO ENW-M2 grant