Blocking regulatory T cells to restore immune function

In this project we examine how regulatory T cells inhibit T helper cells and T cytotoxic cells, how they dampen the immune system and contribute to avoiding autoimmunity as well as how they may be exploited by tumors to evade anti-tumor immunity. We develop methods for turning regulatory T cells on and off. For this purpose, we have established a screening method to search for drug-like compounds that affect formation, activation and function of regulatory T cells, and we have already found some substances. These compounds are being employed as tools to examine regulatory T cell function and characterize their gene signatures, protein expression and how they work in autoimmunity and in evading the immune system in cancer. We will also search for new such substances that can be possible drug candidates. The first compounds we have identified have effects in animal experiments, and we now pursue further investigation both in animal disease models and in patient samples.

Immune suppressive mechanisms serve several important biological functions in the human body which includes controlling autoimmunity and minimizing harmful side effects, inflammation and tissue damage in the course of healthy and successful immune responses to pathogens. These mechanisms that prevent immunological overshoot can be hijacked by growing tumor cells resulting in activation of immune escape which is a crucial process in tumorigenesis. The role of regulatory T-cells (Tregs) in immune escape is of special interest since many of the targets of immunotherapy, like CTLA4, PD1, TIM3 and LAG3, are also shared with regulatory T cells, making it critical to decipher their role in the immune response in order to fully utilize the potential of immune modulating agents. While Treg subsets are well described and their role in different contexts unraveled particularly in mouse models, the understanding of their mode of action and down-stream effector molecules that support different suppression mechanisms in Tregs is less known and drug targeting efforts have not been successful. In this project we will characterize human Tregs during activation. We will apply our new and unique Treg inhibitor tool compounds and methodical set up in order to identify the molecular machinery involved in the different suppressive mechanisms of Tregs. We will also examine the role of Tregs in a clinical context using both established animal models and patient samples. Lastly we will use the Treg inhibitor tools to search for series of more drug-like structures. Understanding how activation of Tregs affects different downstream signaling pathways depending on the intensity of the activation and identification of potential compounds that can modulate this activity will open up new therapeutic avenues. Further the insight gained in this project will allow for precise immune profiling and targeting of the Treg function which is necessary for further advancement in the field of immunotherapy.