| First Author | Tauriello DVF | Year | 2018 |
| Journal | Nature | Volume | 554 |
| Issue | 7693 | Pages | 538-543 |
| PubMed ID | 29443964 | Mgi Jnum | J:261811 |
| Mgi Id | MGI:6154802 | Doi | 10.1038/nature25492 |
| Citation | Tauriello DVF, et al. (2018) TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554(7693):538-543 |
| abstractText | Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFbeta levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFbeta-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFbeta unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFbeta signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFbeta in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFbeta signalling may therefore have broad applications in treating patients with advanced colorectal cancer. |
