TGFß, a Potent Regulator of Tumor Microenvironment and Host Immune Response, Implication for Therapy

Alterations in TGFß signaling are common in human cancers. TGFß has significant impact on tumor initiation and progression. Therapeutic strategies including neutralizing antibodies and small molecular inhibitors have been developed to target TGFß signaling. However, TGFß can work as both a tumor suppressor and a tumor promoter. A significant challenge to the development of successful TGFß antagonism treatment is understanding how and when TGFß switches its function from a tumor suppressor to a tumor promoter. Recent studies demonstrate that TGFß regulates the infiltration of inflammatory cells and cancer associated fibroblasts into the tumor microenvironment, resulting in changes in signaling cascade in tumor cells. Additionally, TGFß exerts systemic immune suppression and significantly inhibits host tumor immune surveillance. Neutralizing TGFß in preclinical mouse models enhances CD8+ T-cell and natural killer cell-mediated anti-tumor immune response. This new understanding of TGFß signaling in regulation of tumor microenvironment and immune response may provide useful information, particularly for patient selection and inflammation/immune biomarkers for TGFß antagonism therapy in clinical trials.