Functional genomic studies of cancer immune evasion using in vitro and in vivo CRISPR/Cas9 genetic screens

Abstract

Recent advances in cancer immunology have shed light on the mechanisms that regulate the interaction of the immune system with cancer, along with the strategies of immune evasion that cancer cells employ in order to survive in the presence of anti-cancer immune responses. An accumulation of data in recent years has identified several immune checkpoint molecules, whose normal role is to down-regulate immune responses in order to maintain immune homeostasis. Expression of these molecules by cancer cells allows them to efficiently evade anti-cancer immune responses. The great potential of these findings is highlighted by the recent approval of therapeutic antibodies targeting and blocking immune checkpoint molecules. Examples include inhibitors of programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), for the treatment of various cancers. Development of novel immunotherapies constitutes an extremely promising clinical development. The advent of CRISPR/Cas9 genome editing technologies and their application in forward genetic screens have revolutionised our ability to interrogate the cancer genome and identify genetic vulnerabilities and essentialities. With these in mind, I have carried out in vitro and in vivo CRISPR/Cas9 genome-wide forward genetic screens. These will, on one hand, enable the identification of genes whose knockouts sensitise cancer cells to the immune system. On the other hand, the screens will also allow the characterisation of novel cancer immune evasion pathways. These genes would be ideal candidates as targets of immunotherapeutic strategies. Preliminary data suggest that the targeting of antigen presentation and processing genes is lethal to colon cancer cell lines in vivo. I anticipate that these studies will aid the identification of novel therapeutic cancer targets.