APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant Kras-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This causes an increase in mutational burden in Kras mutant and p53 deleted (KP) tumours and in carcinogen-induced tumours, but these mutations are sub-clonal and do not lead to sensitivity of the autochthonous tumours to immune interventions. However, when clonal cell lines are derived from these tumours they provide an immunogenic syngeneic transplantation lung cancer model that is sensitive to immunotherapy. The ability of a KRAS-G12C inhibitor to cause regression of these tumours is markedly potentiated by the adaptive immune system, providing an opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer. ### Competing Interest Statement J.D. has acted as a consultant for AstraZeneca, Bayer, Jubilant, Theras, Vividion and Novartis. R.S.H is a co founder, shareholder, and consultant of ApoGen Biotechnologies Inc. S.R. is an employee of AstraZeneca. C.S. receives grant support from Archer Dx, AstraZeneca, BoehringerIngelheim and Ono Pharmaceutical; has consulted for AstraZeneca, Bicycle Therapeutics, Celgene, Genentech, GRAIL, GSK, Illumina, Medicxi, MSD, Novartis and the Sarah Cannon Research Institute; receives grant support and has consulted for Bristol Myers Squibb, Pfizer and RocheVentana; is an advisory board member and is involved in trials sponsored by AstraZeneca; has stock options in Apogen Biotechnologies, Epic Sciences, GRAIL; and has stock options and is a cofounder of Achilles Therapeutics. The other authors declare that they have no competing interests.