Serpin A1 Cargo Within Tumour‐Derived Extracellular Vesicles Supports Pro‐Tumoural Bias of Neutrophils in Cancer
Maksim Domnich, Ekaterina Pylaeva, Elena Siakaeva, Nastassia Kabankova, Agnieszka Bedzinska, Damian Sojka, Aneta Zebrowska, Marta Gawin, Maren Soldierer, Yaping Yu, Malwina Rist, Daniel Fochtman, Bernd Giebel, Iris Helfrich, Ilona Thiel, Basant Kumar Thakur, Cornelius H. L. Kürten, Helmut Hanenberg, Sonja Ludwig, Piotr Widlak, Stephan Lang, Monika Pietrowska, Jadwiga JablonskaABSTRACT
Tumour‐derived extracellular vesicles (EVs) or exosomes are critical mediators of the cancer‐immune system crosstalk, yet the mechanisms by which they reprogram neutrophil function in vivo remain insufficiently characterised. Here, we identify the serine protease inhibitor Serpin A1 as a predominant cargo component of small EVs (sEVs) released by head and neck cancer cels (HNC) and show that this molecule is both necessary and sufficient to confer a stable pro‐tumoural programming of neutrophils. Uptake of Serpin A1‐enriched sEVs elicits extensive proteomic remodelling in neutrophils including activation of STAT3 signalling, leading to sustained induction of PD‐L1, increased Arginase 1 production and prolonged neutrophil lifespan. Functionally, these reprogrammed neutrophils acquire a capacity to drive epithelial‐mesenchymal transition in tumour cells, and to impose exhaustion of T cells via metabolic restriction and arginine depletion, leading to their reduced cytotoxicity. Genetic ablation of Serpin A1 from tumour‐derived sEVs or pharmacologic inhibition of serpin‐STAT3 axis restores neutrophil anti‐tumour functions. Collectively, these findings delineate a Serpin A1‐STAT3/Arginase 1 as an important signalling pathway through which tumour‐derived sEVs promote neutrophil‐dependent immune suppression and tumour progression, and highlight EV‐associated serpins as potential targets for future therapeutic intervention in cancer.