Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

Tumor cells are intrinsically immunogenic because of their mutational burden. 'Driver' mutations disrupt their ability to respond to normal growth regulatory signals whereas 'passenger' mutations occur at random throughout the genome and are unique to a given tumor. Some of these mutations change the coding sequence of an expressed protein, resulting in the generation of nonself-peptides that can be presented at the cell surface as neoantigenic MHC-peptide complexes or neoepitopes [157] . In order to avoid immune detection and destruction, cancers must therefore evade the immune system, which they do very effectively. Thus, tumors lack lymphatic channels and sustain high interstitial pressures, impeding leucocyte extravasation. They release immunosuppressive substances such as prostaglandin E2 and TGFβ and reprogram macrophages from M1 to M2 phenotypes, destroying their ability to process and present tumor antigens. They may even lose the ability to present MHC-peptide complexes on the tumor cell surface [158] . Many tumor review Maroun, Muñoz-Alía, Ammayappan, Schulze, Peng & Russell future science group cells also overexpress PD-L1 and B7.1 receptors on their surface as a last line of defense against attacking T lymphocytes. These checkpoint receptors interact with PD-1 or CTLA4 on the surface of approaching T cells, leading to T-cell anergy. Checkpoint inhibitor anti bodies, which are currently transforming the field of immunooncology, block these PD-1/PD-L1 and/or CTLA4/B7 interactions thereby 'unveiling' the cancer and rendering it susceptible to T-cellmediated killing [159] . Because of their ability to amplify immune-mediated killing of uninfected tumor cells, OVs may be ideal partners for checkpoint inhibitor antibody therapy and can be engineered in various ways to maximize their immune enhancing properties [13, 160] .