Project Summary Lung cancer is the leading cause of cancer related deaths worldwide, demonstrating the pressing need for effective and lasting treatments. Immune checkpoint inhibitors, which block negative regulators of T cell function, have the potential to generate lasting responses in lung cancer patients. However, only a minority of patients respond to these therapies and ~50% of patients whose tumors initially respond to therapy eventually develop acquired resistance. Clinical studies have identified correlations between tumor non-synonymous mutation burden and response to immune checkpoint inhibitors across multiple cancer types. However, most existing pre-clinical mouse models of lung cancer do not recapitulate the complexity of mutational landscapes in human cancers, and importantly, the tumors in these models do not respond to immune checkpoint inhibition. Due in part to the lack of available models, mechanisms of primary and acquired resistance to immune checkpoint inhibition in lung cancer are not fully understood and strategies to overcome resistance are lacking. To address this challenge, we developed novel orthotopic mouse models of Kras mutant lung adenocarcinoma that recapitulate features of human disease essential for studying tumor-immune interactions, including the tumor mutational landscape as well as responsiveness and acquired resistance to immune checkpoint inhibition. Using these novel models of murine lung cancer, my goal is to investigate mechanisms of resistance to these new widely-used lung cancer therapies (F99 phase). I will test the overarching hypothesis that diverse genetic alterations and transcriptional programs resulting in antigen presentation defects and neoantigen loss are major mechanisms of acquired resistance to ICIs and that these drive the emergence of tumor-cell extrinsic features of resistance in the tumor microenvironment. I will investigate the spectrum of genetic and transcriptional drivers of acquired resistance, focusing on defects in antigen processing and presentation (Aim 1.2.A). I will also investigate whether neoantigen loss can mediate acquired resistance in lung cancer (Aim 1.2.B). As a post-doc (K00 phase), I plan to work on approaches to improve immunotherapies for lung cancer to expand their benefits to a broader patient population than those who currently benefit, specifically by investigating the efficacy of personalized neoantigen vaccines that induce tissue resident memory T cells (Aim 2). The aims described here will identify drivers of resistance to checkpoint therapy and explore methods to use neoantigen vaccines in patients that currently do not benefit from approved immunotherapies, yielding strategies to expand immunotherapy benefits to a broader patient pool.