Validation of AGK knockout as a target of Immune Checkpoint Blockade therapy for Colorectal cancer.

Abstract

The evolution of tumor-immune interactions from tumor protective to tumor promoting, has been of recent interest in the field. The immune system plays a significant role in the tumor initiation, promotion/maintenance, and metastasis/growth, as observed in multiple cancers including colorectal cancer. Immunotherapies targeting checkpoint inhibitors (anti-PD1/PDL1, anti-CTLA4) show efficacious results in both patient treatments and clinical trial studies in some cancers like multiple myeloma and advanced lung cancer, but not in all. This is further complicated by tumor resistance to existing therapies and their consequent failures. Therefore there is a constant need to search for novel targets with a translational application. Colorectal cancer still remains a huge burden on the human population. With the advent of CRISPR technology and possibility to perform genome wide CRISPR screens, novel therapeutic targets can be discovered using in vivo mouse model systems with the potential to work in conjunction with anti-PD1/PDL1 and anti-CTLA4 treatment. Based on a previously performed kinome screen, this thesis attempts to validate the functional role of AGK knockout as a potential therapeutic target of Immune checkpoint blockade therapy for colorectal cancer, using mice derived organoids as model system.