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 Foukas, Aristides G. Eliopoulos, Aikaterini Hatzioannou, Themis Alissafi, Michael L. Dustin, Panayotis Verginis
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.