Identification of small-molecule modulators that enhance the ability of the immune system to eliminate cancer cells

Abstract

The ability of the immune system to fight cancer is long-established whereas an in-depth understanding of how cancer cells can escape from immunosurveillance has only emerged over the last 20 year. This led to the development of the first groundbreaking cancer immunotherapies. However, the variety of cancer cell escape mechanisms is still not entirely elucidated, e.g., how cancer cells establish their immunosuppressive tumor microenvironment (TME). Although key components of the TME have been identified, only a few could be established as drug targets for the development of novel small-molecule drugs. To discover new mechanisms to modulator the immunosuppressive features of the TME, two chemical genetic approaches were developed in the course of this thesis. The TME harbors various tumor-derived suppressive factors that inhibit effector immune cells, like natural killer (NK) cells, from eliminating cancer cells. In order to prevent NK cell suppression within the TME and to identify proteins or pathways involved in NK cell inhibition, a phenotypic assay was developed that facilitated the investigation of a small molecule library. In addition, the kynurenine (Kyn) metabolic pathway and its rate limiting enzyme indolamine 2, 3-dioxygenase (IDO1) plays a key role in immunosuppression within the TME. To prevent IDO1 activity a new cell-based assay was established to screen for small-molecule modulators that inhibit the Kyn pathway. Thereby, iDeg-1 was identified, the first monovalent small molecule degrader of IDO1.