IL-3 signalling in the tumour microenvironment shapes the immune response via tumour endothelial cell-derived extracellular vesicles. (May 2022)

• Record Type: Journal Article
• Authors: Lopatina, Tatiana; Koni, Malvina; Grange, Cristina; Cedrino, Massimo; Femminò, Saveria; Lombardo, Giusy; Favaro, Enrica; Brizzi, Maria Felice
• Is Part Of: Pharmacological research. Volume 179(2022)
• Publication Date: 2022-05
• Subjects: Extracellular vesicles -- IL-3 -- Tumour microenvironment -- PD-L1 -- Tumour endothelial cells -- Tumour immune editing; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106206
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Antibody-based anti-cancer therapy is considered a successful approach to impair tumour progression. This study aimed to investigate the clinical impact of targeting the IL-3 signalling in the microenvironment of solid tumours. We intended to investigate whether the IL-3Rα blockade on tumour-derived endothelial cells (TEC) can modulate PD-L1 expression in tumour cells and peripheral blood mononuclear cells (PBMC) to reshape the anti-tumour immune response. Extracellular vesicles released by TEC after IL-3Rα blockade (aTEV) were used as the ultimate effectors of the antibody-based approach, while naive TEC-derived extracellular vesicles (nTEV) served as control. Firstly, we demonstrated that, either directly or indirectly via nTEV, IL-3 controls the expression of its receptor on TEC and PBMC respectively. Moreover, we found that nTEV, moulded by the autocrine secretion of IL-3, increased PD-L1 expression in myeloid cells both in vitro and in vivo . In addition, we found that nTEV-primed PBMC favour tumour cell growth (TEC and MDA-MB-231 cells), whereas PBMC-primed with aTEV still retain their anti-tumour properties. Isolated T-cells pre-conditioned with nTEV or aTEV and co-cultured with TEC or MDA-MB-231 cells have no effects, thereby sustaining the key role of myeloid cells in tumour immune editing. In vivo nTEV, but not aTEV, increased the expression of PD-L1 in primary tumours, lung and liver metastases. Finally, we demonstrated that the enrichment of miR-214 in aTEV impacts on PD-L1 expression in vivo . Overall, these data indicate that an approach based on IL-3Rα blockade in TEC rearranges EV cargo and may reshape the anti-tumour immune response. Graphical Abstract: TL was involved in conceptualization, methodology, data curation and writing the original draft; MK provided formal analysis of in vitro and in vivo experiments; CG performed in vitro and in vivo experiments and provided formal analysis of the in vitro and in vivo studies; MC performed the animal studies; SF isolated and characterized extracellular vesicles; GL performed the animal study; EF performed in vitro studies; MFB was involved in conceptualization, supervision, writing, review and editing the Ms, as well as in providing resources. ga1 Highlights: Extracellular vesicles derived from tumour endothelial cells favour immune suppression. IL-3 induces the expression of PD-L1 through tumour endothelial cell-derived extracellular vesicles. Blocking IL-3 signalling in the TME reshapes tumour endothelial cell-EV cargo and rebuilds the anti-tumour immune response.