Integrin αvβ6 is a heterodimeric cell surface protein that is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Furthermore, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinomas. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which is secreted into the extracellular matrix as an inactive protein complex that requires activation to elicit downstream signaling. TGF-β has recently been shown to inhibit the T-cell anti-tumor response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this project, we investigate the effect of integrin αvβ6 on TGF-β signaling, anti-tumor immune response and tumor growth in colorectal cancer (CRC). We further explore the possibility to enhance current immunotherapies by combining them with blockade of integrin αvβ6. Finally, we examine integrin αvβ6 expression levels in human CRC tumors and the effect of integrin αvβ6 on survival and anti-tumor immune response in the patients. Together, this translational research project might provide with a new option for immunotherapy in CRC based on integrin αvβ6 blockade.