Extracellular Vesicles of Salivary Adenoid Cystic Carcinoma Suppress Immune Microenvironment in Lung

Salivary adenoid cystic carcinoma (SACC) frequently metastasizes to the lung and affects patient survival. Extracellular vesicles (EVs) have significant effects in the tumor pre-metastatic niche (PMN). In this study, we aimed to investigate immune changes in the lung pre-metastatic microenvironment of SACC. A pre-metastatic microenvironment was established using SACC-derived EVs at different time points. Labeled EVs were injected into mice to examine their different organ distributions. Flow cytometry was conducted to analyze the immune cell populations. In vitro, the same amount of SACC-derived EVs or EV-depleted conditional medium was added to macrophages to stimulate polarization. The SACC-derived EVs colonized mostly in the lung and were engulfed by lung interstitial macrophages (IM). At different time points, the SACC-derived EVs induced decreased total macrophage, natural killer cell, and T cell populations, especially CD8+ T cells. They also increased the M2 macrophage composition and regulatory T cell population. The in vitro study showed that SACC-derived EVs induce a mixed M1/M2 phenotype, but this effect was eliminated with the EV-depleted media. SACC-derived EVs circulate to the lung, where they are engulfed by IM and induce an immunosuppressive environment. In vitro experiments revealed that cargos on EVs could mediate macrophage polarization.