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

Author

Listed:
  • Ankur Chakravarthy

    (University Health Network
    University of Toronto)

  • Lubaba Khan

    (University of Calgary
    University of Calgary
    University of Calgary)

  • Nathan Peter Bensler

    (University of Calgary
    University of Calgary
    University of Calgary)

  • Pinaki Bose

    (University of Calgary
    University of Calgary
    University of Calgary
    University of Calgary)

  • Daniel D. De Carvalho

    (University Health Network
    University of Toronto)

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.

Suggested Citation

  • Ankur Chakravarthy & Lubaba Khan & Nathan Peter Bensler & Pinaki Bose & Daniel D. De Carvalho, 2018. "TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06654-8
    DOI: 10.1038/s41467-018-06654-8
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    Cited by:

    1. E. H. Puttock & E. J. Tyler & M. Manni & E. Maniati & C. Butterworth & M. Burger Ramos & E. Peerani & P. Hirani & V. Gauthier & Y. Liu & G. Maniscalco & V. Rajeeve & P. Cutillas & C. Trevisan & M. Poz, 2023. "Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Jingjing Qi & Hongxiang Sun & Yao Zhang & Zhengting Wang & Zhenzhen Xun & Ziyi Li & Xinyu Ding & Rujuan Bao & Liwen Hong & Wenqing Jia & Fei Fang & Hongzhi Liu & Lei Chen & Jie Zhong & Duowu Zou & Lia, 2022. "Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Jiaye Liu & Yang Wang & Chunyang Mu & Meng Li & Kewei Li & Shan Li & Wenshuang Wu & Lingyao Du & Xiaoyun Zhang & Chuan Li & Wei Peng & Junyi Shen & Yang Liu & Dujiang Yang & Kaixiang Zhang & Qingyang , 2022. "Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Youya Nakazawa & Masayuki Miyano & Shuntaro Tsukamoto & Hiroyuki Kogai & Akihiko Yamamoto & Kentaro Iso & Satoshi Inoue & Yoshinobu Yamane & Yuki Yabe & Hirotatsu Umihara & Junichi Taguchi & Tsuyoshi , 2024. "Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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