6533b839fe1ef96bd12a5fa4

RESEARCH PRODUCT

COLON CANCER CELL-DERIVED EXOSOMES INDUCE MACROPHAGES TO ACQUIRE AN IMMUNOSUPPRESSIVE PHENOTYPE BY UPREGULATING PD-L1 EXPRESSION

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Tumor-associated macrophages (TAMs) are a prominent component of cancer microenvironment having a key role in promoting tumor progression. Several studies have demonstrated that TAMs phenotypically and functionally correspond to M2-polarized macrophages thus they exert immunosuppressive functions also associated to the expression of programmed cell death ligand 1 (PD-L1). Within the local tumor microenvironment, tumor-derived exosomes (TDEs) are well known to play a key role in modulating the properties and the behavior of surrounding cells such as TAMs. Even if several studies demonstrated the ability of TDEs to induce M2-like macrophage polarization, few data are available about their involvement in regulating the expression of PD-L1 in TAMs. The aim of the current study was to investigate the ability of exosomes derived from SW480 human colon cancer cells to modulate the properties of TAMs by using non-polarized macrophages (M0-M) differentiated from THP-1 as in vitro model. Our results indicate that after 48h treatment, exosomes derived from SW480 cells (SW480exos) significantly upregulate the expression of surface markers of M2-like phenotype (CD163 and CD206) as well as of PD-L1, inducing macrophages to acquire an immunosuppressive phenotype. In parallel, we found that SW480exos were able to induce a significant increase of interleukin 6 (IL6) expression at both mRNA and protein level. Finally, according to the known ability of PD-1/PD-L1 axis to induce T cell dysfunction, we found that CD3+ T cells co-cultured with M0-M pre-treated with SW480exos significantly increased their apoptotic rate in comparison to those grown in presence of no-treated M0-M. Cumulatively, these preliminary data suggest that within local colon cancer microenvironment TDEs can act as positive modulators of the immunosuppressive status of TAMs, actively promoting the immunotolerance necessary to favor tumor growth and progression.