Investigating tumor cell-specific barriers for immunotherapy

Abstract

The notion of harnessing the patient’s intrinsic immune system to target tumor cells has sparked the development of immunotherapy as a promising new approach to treat cancer. However, only a minority of patients benefit from currently available immunotherapeutic approaches, as many tumors escape immune attacks and develop immune evasion mechanisms. Hence, it is crucial to identify cellular factors that influence the success of immune cell-mediated tumor clearance. In this project, I developed a genetically defined autochthonous liver cancer mouse model with conditional neoantigen expression for the investigation of neoantigen-mediated immune responses and immunotherapeutic treatments. In addition to that, I used primary neoantigen-expressing tumor cells and antigen-specific T cells to establish a co-culture assay in order to study mechanisms of cytotoxic T cell-mediated killing. This assay was further used to perform a lentiviral CRISPR/Cas9 screen, which identified new tumor cell-specific mediators of T cell-dependent killing, among others Activin A receptor type I (Acvr1). Additional experiments validated the role of Acvr1, a type I receptor serine kinase of the bone morphogenetic protein (BMP) pathway, in T cell-mediated killing. Moreover, I could show that Acvr1 knock-out reduced T cell killing efficiency by downregulating the expression of the death receptor Fas, thus reducing FAS ligand (FASLG)-mediated apoptosis induction. In summary, this study included the establishment of new in vivo and in vitro model systems for the investigation of neoantigen-specific immune responses and tumor cell clearance. With that, I was able to identify Acvr1 as new mediator of T cell-dependent tumor cell killing and prospective drug target. These findings offer the opportunity to further explore and improve immunotherapeutic approaches to potentially enhance the success rate of immunotherapies in the future