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Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development

Author

Listed:
  • Athina Varveri

    (Biomedical Research Foundation Academy of Athens
    University of Crete)

  • Miranta Papadopoulou

    (Biomedical Research Foundation Academy of Athens
    University of Crete)

  • Zacharias Papadovasilakis

    (University of Crete
    Foundation for Research and Technology)

  • Ewoud B. Compeer

    (University of Oxford)

  • Aigli-Ioanna Legaki

    (Biomedical Research Foundation Academy of Athens)

  • Anastasios Delis

    (Biomedical Research Foundation Academy of Athens)

  • Vasileia Damaskou

    (Attikon University Hospital)

  • Louis Boon

    (JJP Biologics)

  • Sevasti Papadogiorgaki

    (University of Crete)

  • Martina Samiotaki

    (Biomedical Sciences Research Centre Alexander Fleming)

  • Periklis G. Foukas

    (Attikon University Hospital)

  • Aristides G. Eliopoulos

    (Medical School National and Kapodistrian University of Athens)

  • Aikaterini Hatzioannou

    (Medical School National and Kapodistrian University of Athens
    University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden)

  • Themis Alissafi

    (University of Oxford
    Medical School National and Kapodistrian University of Athens)

  • Michael L. Dustin

    (University of Oxford)

  • Panayotis Verginis

    (Biomedical Research Foundation Academy of Athens
    University of Crete
    Foundation for Research and Technology
    University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden)

Abstract

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA+ CAFs can form immunological synapses with Foxp3+ regulatory T cells (Tregs) in tumours. Notably, α-SMA+ CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, α-SMA+ CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in α-SMA-expressing CAF clusters. Conditional knockout of Atg5 in α-SMA+ CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent manner.

Suggested Citation

  • Athina Varveri & Miranta Papadopoulou & Zacharias Papadovasilakis & Ewoud B. Compeer & Aigli-Ioanna Legaki & Anastasios Delis & Vasileia Damaskou & Louis Boon & Sevasti Papadogiorgaki & Martina Samiot, 2024. "Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49282-1
    DOI: 10.1038/s41467-024-49282-1
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    References listed on IDEAS

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    1. Taichi Hara & Kenji Nakamura & Makoto Matsui & Akitsugu Yamamoto & Yohko Nakahara & Rika Suzuki-Migishima & Minesuke Yokoyama & Kenji Mishima & Ichiro Saito & Hideyuki Okano & Noboru Mizushima, 2006. "Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice," Nature, Nature, vol. 441(7095), pages 885-889, June.
    2. Wei Tan & Weizhou Zhang & Amy Strasner & Sergei Grivennikov & Jin Q. Cheng & Robert M. Hoffman & Michael Karin, 2011. "Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling," Nature, Nature, vol. 470(7335), pages 548-553, February.
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