{"entity":{"id":"paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","kind":"paper","name":"TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","aka":[],"tldr":"Mice given all four of the main bowel cancer mutations grew tumours that spread and, like most human bowel cancers, ignored immunotherapy. Blocking TGF-beta let the immune system in, stopped the spread, and made the tumours answer checkpoint drugs.","summary":"Mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells were crossed to analyse the interplay between genetic alterations and the tumour microenvironment. Quadruple-mutant mice developed metastatic intestinal tumours displaying key hallmarks of human microsatellite-stable colorectal cancer, including low mutational burden, T-cell exclusion and TGF-beta-activated stroma. Inhibition of the PD-1 and PD-L1 checkpoint provoked only a limited response. Inhibition of TGF-beta unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis, and in mice with progressive liver metastatic disease, blockade of TGF-beta signalling rendered tumours susceptible to anti-PD-1 and anti-PD-L1 therapy. Increased TGF-beta in the microenvironment therefore represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the T-helper-1 effector phenotype.","asOf":"2026-09-24","links":[{"label":"Tauriello et al., Nature 2018: TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","url":"https://doi.org/10.1038/nature25492"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29443964/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["tgfb1","pd1","apc","kras","tp53","smad4"],"drugs":[],"companies":[],"institutions":[],"pathways":["tgf-beta","immune-desert-exclusion","pd1-checkpoint","metastatic-cascade"],"terms":["cold-vs-hot","immune-exclusion","mss-pmmr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2018,"doi":"10.1038/nature25492","pmid":"29443964","authors":"Tauriello DVF, Palomo-Ponce S, Stork D, et al.","paperType":"basic","findings":["Quadruple-mutant mice reproduce microsatellite-stable human disease: low mutational burden, T-cell exclusion, TGF-beta-activated stroma.","PD-1 or PD-L1 blockade alone gave only a limited response.","TGF-beta inhibition prevented metastasis and made liver metastases susceptible to checkpoint blockade."],"whatItMeans":"It is the clearest mechanistic answer to why microsatellite-stable colorectal cancer resists immunotherapy, and the rationale for every TGF-beta plus checkpoint combination now in trials in this disease.","caveats":["Mouse genetics; no clinical trial has yet reproduced the effect in patients.","TGF-beta blockade carries cardiac and epithelial toxicity that has limited the clinical agents."],"changedPractice":false},"route":"/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tgfb1","kind":"target","name":"TGFB1","route":"/targets/tgfb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","route":"/pathways/metastatic-cascade/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"},{"id":"mss-pmmr","kind":"term","name":"Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)","route":"/terms/mss-pmmr/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}