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.
Highlights
Ovarian cancer is the fourth most common female cancer worldwide and has the highest mortality rate of all gynecologic cancers in China [1, 2]
A multiphase case-control study was used to examine differences in the mRNA expression levels of immunity-related genes among healthy peripheral blood lymphocytes (PBLs) treated with different exosomes
A total of 84 key genes involved in mediating the communication between tumor cells and the cellular mediators of inflammation and immunity were screened using the Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR Array in PBLs stimulated by malignant and benign exosomes
Summary
Ovarian cancer is the fourth most common female cancer worldwide and has the highest mortality rate of all gynecologic cancers in China [1, 2]. Many studies have demonstrated that the tumor cell microenvironment plays an important role in ovarian cancer progression [3,4,5]. Many studies have reported that exosomes in the microenvironment, which are secreted by most normal and malignant cells, play critical roles in the occurrence and development of cancer [6,7,8,9]. As a novel mode of intercellular communication, exosomes can shuttle between cells and transmit signals by transporting various bioactive proteins and nucleic acids (e.g., DNA, mRNA, and miRNA) [10, 11]. Andre et al reported that exosomes isolated from ovarian cancer ascites contain antigen-presenting molecules, tetraspanins (CD81), and tumor antigens (Her2/Neu, Mart, TRP, and gp100) [12]. 4,563 proteins, 1,639 mRNAs, and 764 miRNAs have been found in exosomes [14]
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