Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer

SIMPLE SUMMARY: Immunotherapy has yielded exciting results against lung cancer, but its efficacy is limited to a small percentage of patients, highlighting the necessity to develop new experimental approaches. The currently available models for pre-clinical studies fail to reproduce the biological features of human cancers. Genetically engineered murine models (GEMMs) are driven by key mutations identified in patients, but they do not recapitulate the complex mutational landscape of human cancers, thus failing to activate the immune system appropriately. On the other side, carcinogen-induced models have appropriate mutational burden, but they require much longer experimental times and have inconsistency of results. We developed a hybrid model in which lung tumors are driven by genetically engineered oncogenic mutations in mice, with increased mutational load induced by in vivo treatment with a carcinogen. This model more closely mimics the complexity of human lung cancer and is suitable for pre-clinical immunotherapy studies. ABSTRACT: Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen N-Methyl-N-Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies.