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Nat Commun. 2018 Nov 8;9(1):4692. doi: 10.1038/s41467-018-06654-8.

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

Chakravarthy A1,2, Khan L3,4,5, Bensler NP3,4,5, Bose P6,7,8,9, De Carvalho DD10,11.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.
2
Department of Medical Biophysics, University of Toronto, Toronto, M5G 1L7, ON, Canada.
3
Ohlson Research Initiative, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada.
4
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada.
5
Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada.
6
Ohlson Research Initiative, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada. pbose@ucalgary.ca.
7
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada. pbose@ucalgary.ca.
8
Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada. pbose@ucalgary.ca.
9
Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, Canada. pbose@ucalgary.ca.
10
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. daniel.decarvalho@uhnresearch.ca.
11
Department of Medical Biophysics, University of Toronto, Toronto, M5G 1L7, ON, Canada. daniel.decarvalho@uhnresearch.ca.

Abstract

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 BRAF, SMAD4 and TP53 mutations and MYC 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.

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