Tumour cell-derived small extracellular vesicles modulate macrophage immunosuppressive phenotype associated with PD-L1 expression

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Abstract

Introduction: Tumour-associated macrophages (TAMs) play a key role in promoting tumour progression, by exerting an immunosuppressive phenotype associated with M2 polarization and with the expression of CD204 and programmed cell death ligand 1 (PD-L1). It is well known that tumour-derived extracellular vesicles (TEVs) play a pivotal role in the tumour microenvironment, influencing TAM behaviour. The study was aimed to examine the effect of TEVs derived from colon cancer and multiple myeloma cells on macrophage functions.Methods: Non-polarized macrophages (M0) differentiated from THP-1 cells were co-cultured, for 3 up to 48 hours, with TEVs derived from a colon cancer cell line, SW480, and multiple myeloma cell line, MM1.S. The expression of M2 and TAM markers (respectively CD163 and CD204) as well as of PD-L1 and Interleukin 6 (IL6) were evaluated at mRNA and protein level. The apoptotic rate of CD3+ T cells cocultured with TEV-treated M0 macrophages was analysed by FACS.Results: Our results indicate that TEVs can significantly upregulate the expression of surface markers of M2-like phenotype (CD163) and TAM (CD204) as well as of PD-L1, inducing macrophages to acquire an immunosuppressive phenotype. In parallel, we found that TEVs were also able to induce a significant increase of IL6 expression at both mRNA and protein levels and to activate the STAT3 signalling pathway. Since PD-1/PD-L1 axis is involved in the inhibition of T cells, we assessed the ability of macrophages treated with TEVs to affect T cell viability. We found that CD3+ T cells co-cultured with TEVs-treated M0 showed an increase of their apoptotic rate in comparison to CD3 + T cells grown in the presence of untreated macrophages.Summary/Conclusion: Cumulatively, these preliminary data suggest that TEVs contribute to the immunosuppressive status of TAMs, promoting tumour growth and progression.Funding: Grant from the Fondazione AIRC per la Ricerca sul Cancro to Riccardo Alessandro (grant n° 18783).
Original languageEnglish
Number of pages1
JournalJournal of Extracellular Vesicles
Volume9
Publication statusPublished - 2020

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