TGF-beta signaling as a determinant of stroma remodeling and immune response in lung cancer

There is an urgent need to increase the efficacy of immunotherapy and optimize patient selection in the treatment of lung cancer.

This application aims at applying basic knowledge on TGF-beta signaling that exerts context-dependent immune-inhibitory effects, at the level of biomarker and drug targeting.The overall aim is to molecularly define clinically relevant immune-modulatory pathways, that are the consequence of active TGF-beta signaling and are associated with the clinical outcome as well as response to immunotherapy.

This will be achieved in three specific aims:Using advanced in situ techniques on patient tissue that represent different stages of disease (premalignant lesion, in situ cancer, invasive cancers, and metastases), we will characterize the spatial pattern of spatial TGF-beta activation throughout all phases of lung tumorigenesis.Spatial TGF-beta activation patterns will be evaluated in patients receiving immune checkpoint inhibitors.

The association with response and survival will indicate novel therapeutic targets.Using syngeneic mouse models and patient-derived 3D cell cultures we will evaluate the mechanisms of how TGF-beta mediates changes in tumor-stroma interaction and immune response.Ultimately, our studies aim to define the spatial and temporal role of TGF beta activation in human lung cancer and will identify novel immune-regulatory mechanisms with cancer biomarker and drug-target potential.