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. 2017 Jun 1:8:607.
doi: 10.3389/fimmu.2017.00607. eCollection 2017.

Comparative Gene Expression Analysis of Lymphocytes Treated with Exosomes Derived from Ovarian Cancer and Ovarian Cysts

Yujuan Li  1 , Yang Yang  1 , Aiwei Xiong  1 , Xiaoqin Wu  1 , Jingyan Xie  1 , Suping Han  1 , Shuli Zhao  1   2
Affiliations

Comparative Gene Expression Analysis of Lymphocytes Treated with Exosomes Derived from Ovarian Cancer and Ovarian Cysts

Yujuan Li et al. Front Immunol. .

Abstract

Cancer cells employ many strategies to evade immune defense and to facilitate tumor growth and angiogenesis. As a novel mode of intercellular communication, cancer-derived exosomes contribute to the recruitment and mediation of lymphocytes within the tumor environment. However, the mechanisms and key molecules mediating the effect of exosomes on lymphocytes are unclear. We treated healthy peripheral blood lymphocytes with exosomes from ovarian cancer and ovarian cysts and screened for differentially expressed genes using the RT2 Profiler Cancer Inflammation and Immunity Crosstalk PCR Array. A total of 26 upregulated genes (mainly pro-inflammatory genes and immunostimulatory and immunosuppressive factor) and two downregulated genes (antigen presentation HLA-A/B) were identified. Western blotting using lymphocytes from malignant ascites and peritoneal washings of benign ovarian cysts suggested that the interferon and NF-κB signaling pathway were involved in the immune regulation of malignant exosomes. Out of 28 differentially expressed genes detected using the array, 11 were validated by real-time PCR using lymphocytes within ovarian cancer (n = 27) and ovarian cyst (n = 9) environments. In conclusion, our findings indicate that malignant cells secrete exosomes in the tumor microenvironment to recruit lymphocytes in order to suppress antitumor immunity (IL10, Foxp3, and HLA-A/B) and enhance tumor invasion, angiogenesis, and dissemination of proinflammatory cytokines (such as IL6 and VEGFA) via the interferon and NF-κB signaling pathways. These results clarify lymphocyte-cancer cell cross talk via exosomes and may facilitate the development of effective immunotherapeutic strategies for ovarian cancer.

Keywords: exosomes; lymphocytes; ovarian cancer; ovarian cysts; tumor microenvironment.

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Figures

Figure 1
Figure 1
Electron micrograph analyses of exosomes from peritoneal washings (A) and malignant ascites (B). Structural analysis of exosomes shows the presence of vesicles in the size range of 40–120 nm.
Figure 2
Figure 2
Screening using the RT2 Profiler Cancer Inflammation and Immunity Crosstalk PCR Array (PAHS-181Z). Eighty-four cancer-related genes were analyzed using the RT2 Profiler™ PCR Array (n = 3 per group). Finally, 28 genes changed significantly between the malignant exosome group (group 1) and the benign ascite exosome group (control group).
Figure 3
Figure 3
Western blotting assays were used to analyze differences in signaling pathway activity between lymphocytes in malignant ascites of six epithelial ovarian cancer (EOC) patients and peritoneal washings of six benign ovarian cyst patients. The phosphorylation levels of IRF3 and p65 in the nucleus of lymphocytes from malignant ascites were higher than those from benign ascites.
Figure 4
Figure 4
Validation of the PCR screening results. The 28 genes identified using the RT2 Profiler™ PCR array were validated using real-time PCR in lymphocytes from a larger sample of patients [27 epithelial ovarian cancer (EOC) patients and nine benign ovarian cyst patients]. Eleven genes showed significant differences (p < 0.05, t-test).
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