TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure

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<jats:title>Abstract</jats:title><jats:p>The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis. Here we report findings from one of the largest pan-cancer analyses of ECM gene dysregulation in cancer. We define a distinct set of ECM genes upregulated in cancer (C-ECM) and linked to worse prognosis. We found that the C-ECM transcriptional programme dysregulation is correlated with the activation of TGF-β signalling in cancer-associated fibroblasts and is linked to immunosuppression in otherwise immunologically active tumours. Cancers that activate this programme carry distinct genomic profiles, such as <jats:italic>BRAF</jats:italic>, <jats:italic>SMAD4</jats:italic> and <jats:italic>TP53</jats:italic> mutations and <jats:italic>MYC</jats:italic> amplification. Finally, we show that this signature is a predictor of the failure of PD-1 blockade and outperforms previously-proposed biomarkers. Thus, our findings identify a distinct transcriptional pattern of ECM genes in operation across cancers that may be potentially targeted, pending preclinical validation, using TGF-β blockade to enhance responses to immune-checkpoint blockade.</jats:p>

Journal

  • Nature Communications

    Nature Communications 9 (1), 4692-, 2018-11-08

    Springer Science and Business Media LLC

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