Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment

PROJECT SUMMARY/ABSTRACT Brain metastasis (BrM) is the most common intracranial tumor in adults. Despite advanced therapies, BrM remains a major cause of morbidity and mortality in patients with lung cancer. The mechanisms underlying BrM progression and immune evasion remain poorly understood. Fibroblasts are abundant in the lung cancers that have metastasized to the brain, but functions of fibroblasts in BrM are still not known. In our preliminary studies, metastasis-associated fibroblasts (MAFs) promote BrM growth through a soluble form of placental growth factor (PGF). MAF-derived PGF protect cancer cells from treatment with tyrosine kinase inhibitors (TKIs) and induce immunosuppressive environment in BrM. Based on these observations, we propose that MAFs-derived PGF supports BrM growth in two ways: 1) directly by stimulating the proliferation and chemoresistance of cancer cells; 2) indirectly by inducing an immunosuppressive tumor microenvironment. This hypothesis will be tested in two specific aims: 1) determine how MAF-derived PGF directly regulates the proliferation and TKI resistance of cancer cells in BrM. 2) determine how MAF-derived PGF causes immunosuppression in BrM. Our studies will establish the importance of MAF-derived PGF in inducing TKI resistance and immunosuppression in BrM. PGF neutralizing antibodies efficiently penetrate the brain, and already show promise in treating primary brain tumors, both in preclinical studies and in ongoing clinical trials. Our studies will provide strong mechanistic rationale and pave the way for therapeutic use of PGF antibodies in treating BrM.