TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

A combination of TGFβ inhibition and checkpoint-inhibition therapy provokes a potent cytotoxic response against metastatic tumours derived from colorectal cancers in mice. Some types of colon tumour are considered immunologically cold owing to their limited response to immunotherapy. Here, the authors model metastatic colorectal tumours using compound genetic mouse models and organoid transplantation and find that their immunogenicity is at least partly regulated by TGFβ signalling in the tumour microenvironment. Stromal-derived TGFβ seems to regulate T-cell differentiation and exclude immune infiltration from tumours. Inhibition of TGFβ can effectively reduce the growth of metastatic colorectal cancer, and synergizes with anti-PD1 blockade, suggesting potential combination strategies for more potent immunotherapy for colorectal cancer. 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 cancers1,2. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration3, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity2 or increased TGFβ levels4 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 burden5, T-cell exclusion3 and TGFβ-activated stroma4,6,7. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ 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 TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.