ABSTRACT
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 failed to substantially increase clonal tumour mutational burden and autochthonous tumours remained refractory to immunotherapy. However, by establishing clonal cell lines from these tumours we generated an immunogenic syngeneic transplantation model of KRAS mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, we found that anti-tumour immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing versions of these tumours was markedly potentiated by the adaptive immune system, providing a unique 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.
Footnotes
This version of the manuscript has been revised to reflect our finding that endogenous CD8+ T cell responses are directed against derepressed endogenous retrovirus antigens expressed by the KPAR1.3 tumour cell line, but evidence of T cell responses against APOBEC3B induced mutant neoantigens was not found.