Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

TGF beta (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGF beta acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGF beta pathway, and in established tumours, TGF beta then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGF beta is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGF beta is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The alpha v-integrins are major activators of latent-TGF beta. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGF beta is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGF beta, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGF beta in cancer, the role of integrins in activating TGF beta in the TME, and the potential benefits of targeting integrins to augment immunotherapies.