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

Athina Varveri, Miranta Papadopoulou, Zacharias Papadovasilakis, Ewoud B. Compeer, Aigli-Ioanna Legaki, Anastasios Delis, Vasileia Damaskou, Louis Boon, Sevasti Papadogiorgaki, Martina Samiotaki, Periklis G. Foukas, Aristides G. Eliopoulos, Aikaterini Hatzioannou, Themis Alissafi, Michael L. Dustin and Panayotis Verginis ()
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Athina Varveri: Biomedical Research Foundation Academy of Athens
Miranta Papadopoulou: Biomedical Research Foundation Academy of Athens
Zacharias Papadovasilakis: University of Crete
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
Themis Alissafi: University of Oxford
Michael L. Dustin: University of Oxford
Panayotis Verginis: Biomedical Research Foundation Academy of Athens

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49282-1

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