Role of IL-33 in KRAS and STK11 mutant non-small cell lung cancer

Background and innovation Non-small cell lung cancers (NSCLC) with loss-of-function of STK11 and oncogenic KRAS mutations are less likely to respond to anti-cancer immunotherapy. How loss of STK11 reduces the effect of checkpoint inhibitor immunotherapy and the role of mutant KRAS in NSCLC is poorly understood. Our preliminary pre-clinical data suggest a role for tumor derived interleukin- 33 (IL-33) interacting with the host’s immune system, and deleting IL-33 from tumor cells results in slower tumor growth. The proposed translational project aims to use a previously developed novel mouse model with an intact immune system, required for testing of immunotherapy, and implantation of genetically defined, well characterized NSCLC cells with consistent growth patterns to 1) establish a causal link between STK11 mutations and tumor production of IL-33; 2) determine which cells are responsible for responding to tumor produced IL-33 in promoting more rapid tumor growth; 3) test whether blocking IL-33 throughout the whole body has similar effects to preventing tumor cells specifically from releasing IL-33. Significance and Impact to Veterans Healthcare By leveraging the existing infrastructure of the Lung Precision Oncology Program and support of the National Precision Oncology Program for routine comprehensive genomic testing of early- stage lung cancers, a network of five Veterans Affairs Medical Centers in the New York metropolitan area and other VA sites nationwide will provide sufficient samples of NSCLC specimens with STK11 and KRAS alterations from Veterans who are treated with surgical resection of their lung cancer. Path to translation Successful completion of this project will not only drive human clinical trials to test whether targeting IL-33 may work in NSCLC, but will also add to the knowledge of basic tumor biology, including the role of STK11 and IL-33 in NSCLC. Furthermore, this project may establish IL-33 as a biomarker predicting response or even harm to immune checkpoint inhibitors, and if a cell type response for promoting tumor growth is successfully identified could lead to novel treatments for NSCLC.