Therapeutic antibody inhibits target-mediated immune migration in advanced in-vitromodelofanimmune suppressive tumormicroenvironment

It has become increasingly clear that current immune-oncology treatments are inadequate in generating sufficient targeted treatment effects without damaging the surrounding tissue. Rather than focusing on the tumor as the main target, the immune suppressive tumor microenvironment has recently become a novel therapeutic target as it drives tumor growth, therapy resistance and metastasis. However, current in vitro systems often fail to replicate the tumor microenvironment hindering accurate efficacy evaluation. This study used an advanced in-vitro model of an immune suppressive tumor microenvironment to study treatment effects of therapeutic antibodies. Here we report on the use of an organ-on-a-chip based model to study immune cell migration in the context of a subset of immune suppressive macrophages, known as perivascular macrophages (PVM), and on a target protein released by these cells. The model contains an endothelial vessel (HUVEC), macrophages (PVM or M1) and immune cells (PBMCs or T cells) to study the interaction between these cells and determine the effect of target protein and antibodies. The level of immune cell migration showed to be dependent on the activation state of immune cells and pretreatment of the endothelium. PVMs shown to have an inhibitory effect on immune cells migration, in contrast to M1 macrophages that increased the number of migrated immune cells. The released target protein was found to reduce T cell migration, specifically for stimulated T cells. Finally, novel therapeutic antibodies were assessed after addition of the target protein. For one of the antibodies increased migration of stimulated T cells was observed. These findings highlight the potential of targeting PVMs and their released proteins, as important elements of an immune suppressive microenvironment. Additionally, the study shows the utility of the advanced in-vitro model for evaluating therapeutic antibodies. In the future the system will be used for testing additional therapeutics in the context of an immune suppressive tumor microenvironment.