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Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells

Author

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  • Matthew A. Lakins

    (University of Cambridge, Cambridge Biomedical Campus)

  • Ehsan Ghorani

    (University of Cambridge, Cambridge Biomedical Campus)

  • Hafsa Munir

    (University of Cambridge, Cambridge Biomedical Campus)

  • Carla P. Martins

    (University of Cambridge, Cambridge Biomedical Campus)

  • Jacqueline D. Shields

    (University of Cambridge, Cambridge Biomedical Campus)

Abstract

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and “normal” stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.

Suggested Citation

  • Matthew A. Lakins & Ehsan Ghorani & Hafsa Munir & Carla P. Martins & Jacqueline D. Shields, 2018. "Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03347-0
    DOI: 10.1038/s41467-018-03347-0
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    Cited by:

    1. Luigi Mazzeo & Soumitra Ghosh & Emery Di Cicco & Jovan Isma & Daniele Tavernari & Anastasia Samarkina & Paola Ostano & Markus K. Youssef & Christian Simon & G. Paolo Dotto, 2024. "ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Xin Li & Tuying Yong & Zhaohan Wei & Nana Bie & Xiaoqiong Zhang & Guiting Zhan & Jianye Li & Jiaqi Qin & Jingjing Yu & Bixiang Zhang & Lu Gan & Xiangliang Yang, 2022. "Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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