Immune consequences and therapeutic targeting of disrupted RNA splicing in cancer

Abstract

Immunotherapies, such as checkpoint blockade, CAR-T cells, and vaccines, have proven to be a valuable tool to treat various types of cancer. This class of therapy capitalizes on the immune system’s natural ability to recognize foreign antigens and kill cancer cells. Typically, many of these therapies have focused on the changes to DNA, particularly point mutations, that mark cancer cells. However, RNA dysregulation is also a frequent characteristic of cancer, and these transcriptomic changes may provide a large repertoire of new targets that previously has not been well studied. In this thesis, I address the question of whether RNA splicing changes can be immunogenic by studying disrupted splicing arising from 1) pharmacologic manipulation and 2) recurrent driver mutations in splicing factors. I demonstrate that drugs targeting splicing machinery can elicit anti-tumor immune responses dependent on splicing-derived neoantigens, and that checkpoint blockade can be used in combination with these drugs to further improve immune response and tumor clearance. I further provide a framework for identifying splicing-derived neoepitopes and use this framework to identify potential immune targets in splicing factor-mutant cancers. I then use mass cytometry-based approaches with leukemic SF3B1-mutant patient samples to characterize the immune environment in SF3B1-mutant cancers and search for antigen-specific T cells that recognize and respond to splicing-derived neoantigens.