Impact of PDGFRA+ CAFs on Anti-tumor Immunity in the Tumor Microenvironment of Non-Small Cell Lung Cancer

Dr. Herzog is interested in why so many non-small cell lung cancer (NSCLC) patients do not achieve durable responses to immune checkpoint inhibitors, despite the initial benefit.  He is particularly interested in understanding how the non-immune cells in the tumor microenvironment (TME) impact antitumor immunity and he suggests that response to immune checkpoint therapy in lung cancer might be impaired by fibroblasts in the stroma in the TME.  In past studies, Dr. Herzog has found that fibrosis correlates with reduced T cell infiltration and poor clinical outcomes. In preclinical models, lung fibrosis leads to impaired T cell immune surveillance and is often seen with poor dendric cell activation and tumor progression.  Further, in these models, fibrosis completely cancels out the benefit of adding immune checkpoint inhibition to chemotherapy. This all suggests that targeting the fibrotic TME could enhance immunotherapy response. Importantly, he has already shown that depletion of a subset of cancer associated fibroblasts (CAFs) called PDGFRα CAFs improves anti-tumor immunity in patients. 

Now, Dr. Herzog will use his Young Investigator Award to further investigate the role of PDGFRα CAFs in creating an immune suppressive phenotype in macrophages and in reducing dendric cells. He will also explore whether PDGFRα CAFs impair T-cell function and localization.  Dr. Herzog notes that NSCLC tissues have large amounts of fibrosis, including fibroblasts; this project will use multiple approaches to phenotypically, functionally and spatially characterize how PDGFRα CAFs affect macrophages and dendric cells in the NSCLC tumor TME. Dr. Herzog hypothesizes that fibrosis induces the expression of T-cell exhaustion markers, which may be one way T-cells are excluded from the TME when PDGFRα CAFs are present.  By showing that these specialized cancer-associated fibroblasts are implicated in inhibiting T cell activation and changing T cell phenotype, Dr. Herzog hopes to lay the foundation for targeting CAF functions in the tumor microenvironment to make immunotherapy more effective for more patients.