The expression of programmed cell death ligand 1 (PD-L1) in tumors is associated with tumor cell escape from T-cell cytotoxicity, and is considered a crucial effector in chemoresistance and tumor relapse. Although PD-L1 induction has been observed in patients after chemotherapy treatment, the mechanism by which the drug activates PD-L1 expression remains elusive. Here, we identified the extracellular vesicles (EVs) as a molecular mediator that determines the effect of doxorubicin on PD-L1 expression in osteosarcoma models. Mechanistically, doxorubicin dependently stimulates the release of extracellular vesicles, which mediate autocrine/paracrine signals in osteosarcoma cells. The recipient cells were stimulated by these EVs and acquired the ability to promote the expression of inflammatory cytokines interleukin (IL)-1β and IL-6. In response to doxorubicin, IL-1β, but not IL-6, allowed- osteosarcoma cells to promote the expression of PD-L1, and the elimination of IL-1β/IL-1 receptor signaling with IL-1 receptor antagonist reduced PD-L1 expression. Together, these findings provided insights into the role of EV release in response to chemotherapy that mediates PD-L1 expression via the IL-1 signaling pathway, and suggested that the combination of a drug targeting IL-1 or PD-L1 with chemotherapy could be an effective treatment option for osteosarcoma patients.

The objective of this research work is to propose a phase diagram that can be used to find a proper operating condition for generating droplets of different types. It is found that the phase diagram of Q_R versus Ca_D can effectively classify the droplet generation into three vivid regimes: dripping, jetting and tubing. For the dripping regime, its operating condition is in the range of either Ca_D < 10⁻⁴ and Q_R < 50 or 10⁻³ < Ca_D < 10⁻⁴ and Q_R < 1. For the jetting regime, its operating condition is in the range of either Ca_D < 1.35 × 10⁻² and Q_R > 100 or Ca_D > 1.35 × 10⁻² and Q_R > 1. For the tubing regime, its operating condition is in the range of Ca_D > 1.35 × 10⁻² and Q_R < 1.