Background: Peritoneal dissemination is a common mode of tumor progression in ovarian cancer, and one of the most important unfavorable prognostic factors. Epithelial-mesenchymal transition (EMT) has been indicated to be a key process in tumor invasion and metastasis. Recent studies demonstrate that EMT suppresses anti-tumor immunity in some types of cancer. The aim of the current study is to elucidate the relationship between EMT-related gene Snail and local immunity in ovarian cancer.
Methods: The expression of Snail and patient survival was analyzed in two microarray datasets, TCGA, and KOV75 (75 ovarian cancer cases operated in our department).
Using mouse ovarian cancer cell line HM-1, the influence of Snail expression on EMT, peritoneal dissemination, survival, and local immunity was analyzed using both in vitro and in vivo models. Snail-silenced cell line, HM1-sh-snail was established, and compared with the control HM-1.
Results: Among 4 subtypes of high grade serous ovarian cancer, Mesenchymal subtype, which show marked stromal reaction in histopathology, shows the worst prognosis (TCGA, KOV75). Snail expression was significantly high in Mesenchymal subtype (TCGA, p<0.0001; KOV75, p<0.05). High Snail expression was significantly related to short overall survival in TCGA (p<0.05).
In HM1-sh-snail, expression of vimentin and fibronectin was decreased in RT-PCR analysis. Cell migration was inhibited in wound-healing assay (p<0.001), but the cell proliferation was not altered in WST assay. In mouse peritoneal dissemination model, HM1-sh-snail group demonstrated longer survival than the control group (p<0.05). In mouse subcutaneous tumor model, HM-1-sh-snail group revealed smaller tumor than the control group (p<0.05), although there was no difference between two groups in nude mouse model.
Flow cytometric analysis of mouse tumors revealed that infiltration of CD4+ T cells and CD8+ T cells were all increased and MDSCs were decreased in HM1-sh-snail group.
Conclusion: Snail-induced EMT inhibits local immune reaction and promotes peritoneal dissemination in ovarian cancer. Snail may be a potential therapeutic target in ovarian cancer.
Citation Format: Mana Taki, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Junzo Hamanishi, Naoki Horikawa, Ikuo Konishi. Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A56.