Blocking regulatory T cells to restore immune function

Prosjektet tar sikte på å undersøke hvordan regulatoriske T celler hemmer T hjelperceller og T dreperceller, hvordan de demper immunsystemet og bidrar til å unngå autoimmunitet samt hvordan de kan utnyttes av kreftsvulster til å omgå anti-tumor immunitet. Vi utvikler metoder for å skru av og på regulatoriske T celler. For å kunne gjøre det har vi satt opp en metode for å lete etter legemiddellignende substanser som påvirker dannelse, aktivering og funksjon av regulatoriske T celler og vi har allerede funnet noen substanser. Disse substansene bruker vi som verktøy for å undersøke regulatoriske T cellers funksjon og karakterisere deres gen-signatur, proteinuttrykk og hvordan de virker i autoimmunitet og til å omgå immunsystemet ved kreft. Vi vil også lete etter nye slike substanser som kan være mulige legemidler. De første substansene vi har funnet har effekter i dyreforsøk og vi går nå videre med undersøkelser av dette både i ulike dyremodeller og i pasientprøver.

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.