Cancer immunotherapy is emerging as a useful strategy to treat solid tumors and is likely to become central to many oncology treatment regimens in the future. We propose to credential well-established genetically engineered mouse (GEM) models of lung adenocarcinoma (LUAD) as tools to phenotype the tumor immune microenvironment and to test and design therapeutic interventions that incorporate immunotherapies with the objective of prioritizing studies for clinical testing. LUAD is a devastating disease with a 16.8% 5-year survival rate (SEER data 2004-2010). These dismal data underscore the need for novel, transformational approaches to treat this disease. During the past decade, two types of therapeutic approaches have emerged that have the potential to significantly improve survival for patients with LUAD: targeted therapies and immunotherapies. Indeed, advances in our understanding of the molecular genetics of LUAD, have led to the identification of mutations in driver oncogenes in >60% of LUADs. The protein products of a subset of these mutants have been successfully targeted using specific small molecule kinase inhibitors such as erlotinib (EGFR) and crizotinib (EML4-ALK) and these are routinely used in the clinic to treat patients. Targeted therapies, however, are limited by the almost inevitable development of drug resistance on average within a year of starting treatment. Therefore, it is necessary to find ways of optimizing the use of targeted therapies and/or finding new ways of treating the disease. Modulation of immune cell function using cancer immunotherapies can also evoke anti-tumor responses and is emerging as a promising approach to treat advanced lung cancer. As these therapies are being developed and tested for clinical use, it is necessary to determine who is likely to respond to these agents and how to optimize their use in the clinic. Here, we propose to validate GEM models of LUAD representing the main molecular subsets of the disease for studies of immuno-oncology. To do this, we will: 1) Characterize the immune microenvironment in LUAD GEM models induced by common somatic genetic alterations, 2) Establish the functional role of components of the immune system for tumorigenesis and tumor regression in LUAD GEM models and 3) Use LUAD GEM models to evaluate and optimize the efficacy of cancer immunotherapies. These studies will provide us with a comprehensive understanding of the immune microenvironment in LUAD and allow us to identify vulnerabilities that can be targeted for therapeutic intervention. Further, this work will enable us to develop reagents and assays that can be disseminated to standardize the analysis and use of GEMs for the evaluation of cancer immunotherapies both within and outside of the NCI's Oncology Models Forum.
Lung cancer is the leading cause of cancer death in the world. Despite progress in our understanding of the molecular alterations that drive lung tumorigenesis, advanced lung cancer remains an incurable disease. Harnessing the immune system to attack lung cancers is a promising approach. We will combine our knowledge of molecular alterations in lung tumors with analysis of changes in the immune cells present in tumors to develop strategies to counter this disease.
