Deciphering how the APOBEC3 antiviral immune response drives lung cancer.

Lung cancer is often diagnosed at a late stage once tumours no longer respond to treatment. Recent lung cancer screening programmes in the UK do reduce mortality, but deciphering the very early changes in normal tissue that increase cancer risk will further identify novel therapeutic targets for cancer prevention that could substantially reduce cancer-related deaths. My laboratory will focus on increasing our understanding of the changes that occur prior to lung tumour initiation and the evaluation of therapeutics designed to target these changes and prevent lung cancer. The antiviral APOBEC3 (A3) immune response has recently emerged as a potential key player in driving lung cancer. A3 enzymes normally protect us from viral infection. Yet as we age, chronic infection and inflammation can induce aberrant A3 enzyme expression driving cancer. In fact at least 20% of cancers are associated with viral infections, and many show evidence of APOBEC activity such as cervical and head and neck squamous cell carcinomas that have high levels of A3 mutagenesis (APOBEC mutation signatures) due to chronic HPV infection. Despite the presence of A3 mutation signatures, in up to 70% of cancer types, our understanding of how A3 expression affects cancer vaccine efficacy or how to tailor cancer vaccines to target A3 induced mutations has not been explored.
Intriguingly, in certain populations around the world A3 genes are altered in the germline. One A3 germline mutation (A3A/B), is more stable and active than its normal counterpart, and so could be a contributing factor to the increased risk of lung cancer observed in East Asian, Native American, and Oceanic populations where A3A/B is detected most frequently (37 - 93%), compared with African and European populations where it is uncommon (1 - 6%). The precise contexts and mechanisms by which A3 genes increase lung cancer risk are unknown, but with the delineation of these mechanisms we will begin to understand if A3A/B germline...