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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.
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.
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.
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Cold tumours: immune deserts and exclusion, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares The metastatic cascade, SMAD4, TGF-β signalling, TP53.
Shares Immune exclusion, Cold tumours: immune deserts and exclusion, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares Immune exclusion, APC, Cold tumours: immune deserts and exclusion, Hot vs cold tumours.
Shares TGFB1, Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), TGF-β signalling, Colorectal cancer.
Shares Immune exclusion, TGF-β signalling, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares Hot vs cold tumours, Nature, PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-1.