8 TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

Abstract

IntroductionMost patients with colorectal cancer (CRC) 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 TGFβ levels predict adverse outcomes in patients with colorectal cancer. To better understand—and more effectively treat—advanced CRC, we need better research models that recapitulate metastatic disease in an immunocompetent background.Material and methodsHere we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations (Apc, KRas, Trp53, and Tgbr2) in intestinal stem cells. From resulting tumours, we derived mouse tumour organoids (MTOs) and characterised these both in vitro and in vivo, using injections in syngeneic C57BL/6J mice.Results and discussionsQuadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. This was recapitulated in transplantation experiments with MTOs. 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, which prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy.ConclusionOur 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.Thus, our model system serves as a new pre-clinical platform to develop novel (immuno-) therapeutic strategies, which may contribute towards complete and durable responses for large groups of patients with advanced disease.ReferenceTauriello DVF, et al. Nature 2018;554:538–543.