Tumour immunogenicity and features of the tumour microenvironment (TME) are implicated in the variability of clinical response to immune checkpoint blockade, yet the underlying mechanisms are poorly understood. Two studies published in Nature have now independently shown that high transforming growth factor-β (TGFβ) signalling contributes to reduced immune surveillance and lack of therapy response in metastatic colorectal cancer (CRC) and metastatic urothelial cancer (UrC).
invasive tumours were free of infiltrating T cells and invasive tumour margins had high stromal TGFβ activity
Tauriello et al. investigated how genetic alterations and the TME interact in metastatic CRC. A quadruple-mutant mouse model with conditional loss of Apc, Tgfbr2 and Trp53 and conditional oncogenic mutation of Kras targeted to intestinal stem cells developed intestinal tumours and liver or lung metastasis in which invasive tumours were free of infiltrating T cells and invasive tumour margins had high stromal TGFβ activity. When mouse tumour organoids (MTOs) from fresh samples of primary tumours or metastases of these mice were orthotopically transplanted into recipient mice, fully invasive tumours with overt liver metastases developed, all of which showed high stromal TGFβ activity and T cell exclusion and had a low tumour mutational burden (TMB). Treatment of MTO-transplanted mice with the TGFβ receptor type 1 (TGFBR1)-specific inhibitor galunisertib reduced tumour growth and TGFβ response signatures in fibroblasts (F-TBRS) and increased T cell infiltration. To analyse the effect of galunisertib on the development of metastatic disease, mice were inoculated with MTOs through portal vein injections and treated with galunisertib two days after inoculation. Galunisertib-treated mice showed decreased metastatic burden in the majority of mice, leading to full recovery. However, when mice were treated with galunisertib 14 days after inoculation (when metastases had fully established), only a few mice showed complete remission. Mice that were non-responsive showed increased T cell infiltration in metastases in response to galunisertib, and had marked expression of programmed cell death protein 1 (PD1) on infiltrating T cells and recruitment of programmed cell death 1 ligand 1 (PDL1)-positive macrophages. Combination treatment of galunisertib with anti-PDL1 antibodies led to complete tumour rejection.
Mariathasan, Turley, Nickles et al. investigated biomarkers of response in a large cohort of patients with metastatic UrC treated with anti-PDL1 antibodies. Using transcriptome RNA sequencing, they found that responders showed high expression of a gene signature associated with activation of CD8+ T effector cells (CD8+ Teff signature) and a high TMB. Importantly, non-responders showed expression of TGFβ signalling pathway genes. Interestingly, in immune-excluded tumours, in which the CD8+ Teff signature expression was intermediate compared with immune-inflamed (high CD8+ Teff signature) or immune-desert tumours (low CD8+ Teff signature), CD8+ T cells were located very close to the desmoplastic stroma, suggesting a role for TME-derived TGFβ in these tumours. An in-house-generated F-TBRS significantly correlated with non-response in immune-excluded tumours. This correlation was even stronger when high F-TBRS and low TMB were combined in further statistical analysis. Finally, inhibiting TGFβ in combination with PDL1 blockade in mouse models of immune-excluded mammary carcinoma and CRC significantly reduced tumour growth, increased T cell infiltration and increased expression of the CD8+ Teff signature.
Both of these studies suggest that high TGFβ activity in the TME is associated with tumours that have T cell exclusion and can be targeted therapeutically. Inhibition of TGFβ signalling in patients with tumours resistant to PDL1 blockade might be a good strategy to improve clinical outcomes in these patients.
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018)
Mariathasan, S., Turley, S. J., Nickels, D. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018)
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Harjes, U. Tear down this wall. Nat Rev Cancer 18, 205 (2018). https://doi.org/10.1038/nrc.2018.22