Priming Cancer Cells for Detection by the Immune System

ASPIRE Award (2019-2020)

Kevan Shokat, PhD, University of California, San Francisco

The adaptive immune system plays an important role in fighting cancer by detecting and destroying cells that have accumulated potentially dangerous mutations. The major histocompatibility complex class I (MHC class I) proteins, which are expressed on the surface of most cells in the human body, are key to this process. These complexes bind to peptides generated within the cell and shuttle these peptides to the exterior surface of the cell. Once on the surface, peptides that contain mutations can be recognized by the T cells responsible for eliminating unhealthy cells. Unfortunately, MHC class I molecules do not bind efficiently to many of the peptides containing the most common oncogenic mutations, enabling these tumors to evade immune detection. This inability of MHC class I proteins to present mutated peptides is a major reason that immune checkpoint inhibitor drugs fail to help a majority of cancer patients. Researchers in the Shokat lab are developing therapeutic strategies to improve MHC class I presentation of mutant peptides produced by two notoriously undruggable, cancer-causing variants of the KRAS gene—G12V and G12D. These mutations are responsible for many common and aggressive cancers including pancreatic, colorectal, and non-small cell lung cancer. The Shokat lab has extensive expertise in targeting RAS-driven cancers. If successful, they expect that this method could be applicable to other common cancer mutations, leading to targeted anti-cancer drugs that allow the immune system to destroy tumor cells that usually resist targeted therapies.