Abstract Patients with KRAS-mutated lung cancer have the poorest prognosis and poor response rates to standard cancer treatments. Concurrent LKB1 or TP53 mutations in KRAS-mutated non-small cell lung cancer (NSCLC) define different subgroups of KRAS-mutant NSCLC. There is an urgent need to identify key therapeutical targets in NSCLC. Type I interferons (IFNs), of which the most well-studied are IFNα/β, are known for their anti-viral activities but also play an important role in cancer. IFNε, a unique type I IFN, shares only 30% amino acid homology with IFNα/β and is constitutively expressed in epithelium of mucosal tissues including lung. We have shown that IFNe exhibits distinct functions from IFNa, modulates production of reactive oxygen species and cytokines/chemokines in primary macrophages, and maintains tissue structure and immune homeostasis in mice. Our recent data show that IFNε, overexpressed in cervical cancer tissues, is required for HeLa cell tumorigenic activities and xenograft tumor growth, indicating a novel role of IFNε in tumorigenesis. Moreover, IFNε expression is detected in normal lung tissues and upregulated in KRAS-driven lung tumors. Higher expression of IFNε is associated with poorer survival in lung cancer patients. Given the importance of conventional type I IFNs (e.g., IFNα/β) in tumorigenesis and anti-cancer treatment, understanding the role of IFNε in lung cancer is crucial for identifying new anti-tumor targets. In this proposal, we will determine intrinsic and systemic functions of IFNε in KRAS-driven lung cancer using well-established genetically engineered mouse models of KRAS-driven NSCLC. Our central hypothesis is that aberrant expression of intracellular and extracellular IFNe contributes to lung tumorigenesis by modulating cellular and immune functions. In Aim 1, we will determine the role of tumor-intrinsic IFNε on KRAS-driven lung tumorigenesis. In Aim 2, we will determine the role of systemic IFNε in KRAS-driven lung tumorigenesis. In Aim 3, we will determine whether systemic IFNε deficiency increases the sensitivity of established KRAS-driven lung tumors to immune check blockades. We expect the results of this study will reveal novel cellular and immunological roles of IFNe in KRAS-mutant NSCLC. Identification of IFNe-mediated cellular and immune targets important for tumorigenesis will offer new avenues for development of therapeutic strategies for lung cancer.

Project Narrative Lung cancer remains the most diagnosed cancer and the leading cause of cancer mortality worldwide. Non- small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. IFNe, a unique type I IFN and constitutively expressed in the epithelium of mucosal tissues, is involved in cervical tumorigenesis. IFNe is expressed in healthy lung tissues and lung tumors but the mechanisms by which IFNe mediates KRAS-driven lung tumorigenesis remain elusive. The goal of this proposal is to determine the role of intrinsic and systemic IFNe in lung cancers and its impact on cancer treatment. The studies will provide insights into developing new preventive and treatment strategies by modulating mucosal immunity.