An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinationsMore about Open Access at the Crick
Authors listJesse Boumelha Sophie de Carne Emily K Law Pablo Romero-Clavijo Matthew A Coelho Kevin Ng Edurne Mugarza Christopher Moore Sareena Rana Deborah Caswell Miguel Murillo David Hancock Prokopios P Argyris William L Brown Cameron Durfee Lindsay K Larson Rachel I Vogel Alejandro Suárez-Bonnet Simon Priestnall Phil East Sarah J Ross George Kassiotis Miriam Molina Arcas Charles Swanton Reuben Harris Julian Downward
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Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor 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 tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, anti-tumor 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 tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.
Journal Cancer Research
Issue number 19