| Ovarian cancer is one of the deadliest gynecological malignancies,with 239,000 new cases and 152,000 deaths worldwide annually,making it the second leading cause of gynecological cancer death.Despite advances in technology that have led to significant improvements in the survival rates of many cancers,the survival rate of ovarian cancer has only increased slightly over-the past few decades.The main treatment methods for ovarian cancer have remained tumor debulking surgery and combination platinum-paclitaxel chemotherapy.Therefore,there is an urgent need to develop new therapies to improve the prognosis of ovarian cancer patients.In recent years,novel immune therapies such as immune checkpoint inhibitors,tumor neoantigens,and CAR-T have achieved great success in some cancers.However,due to the lack of sufficient effector T cell infiltration in ovarian cancer patients,only a small subset of patients can benefit from these new immune therapies.Therefore,identifying targets that can promote effector T cell infiltration is a promising direction to improve the prognosis of ovarian cancer patients.Type Ⅰ interferon has a dual regulatory effect on tumors.On the one hand,it can inhibit tumor cell proliferation,enhance tumor cell immunogenicity,and promote the infiltration of effector T cells.On the other hand,it can promote tumor metastasis and immune escape.Although Type Ⅰ interferon has contradictory effects on tumors,recent studies have shown that inducing tumor cells to secrete Type Ⅰ interferon in mouse tumor models can promote the infiltration of effector T cells,significantly inhibit tumor growth,and prolong the survival of mice.This indicates that inducing tumor cells to secrete type Ⅰinterferon has a positive effect on inhibiting certain tumors overall.However,the mechanism of regulating tumor cell secretion of type Ⅰ interferon is still not clear and requires further research.Due to the dual effects of Type Ⅰ interferon on tumors,we first investigated whether there is a difference in the survival of ovarian cancer patients with high and low expression of Type Ⅰ interferon.For this purpose,we obtained RNA sequencing data and corresponding patient survival data for 375 ovarian cancer samples from a public cancer genomics database.To avoid interference caused by mutations in interferon signaling pathway proteins and other factors that may prevent the transmission of interferon signals downstream,we directly used the expression of core interferon-stimulated genes to reflect the effect of interferon on tumors.After using consistent clustering methods,the 375 ovarian cancer samples were divided into high and low interferon signaling expression groups,and it was found that patients in the high interferon signaling expression group had a better prognosis.Further analysis showed that compared with the low interferon signaling expression group,the differentially expressed genes in the high interferon signaling expression group were mainly enriched in immune responses against foreign substances,and interferon-stimulated exonuclease gene 20(ISG20)was identified as a key gene regulating this immune response.We then found that patients in the high ISG20 expression group had more effector T cells infiltrating their tumors and stronger tumor immunogenicity.Furthermore,we found that overexpression of ISG20 in ovarian cancer cell lines can induce the secretion of interferon beta.Finally,we found that ISG20 upregulates interferon beta expression by producing more short double-stranded RNA fragments by its nucleic acid nuclease activity,which are recognized by the retinoic acid-inducible gene-Ⅰ.In summary,our study provides a bioinformatics analysis method for evaluating the effects of interferon on tumors.We also found that ISG20 can promote the secretion of interferon beta in ovarian cancer to regulate anti-tumor immune responses,providing new insights into the mechanism of regulating the secretion of Type Ⅰ interferon by tumor cells and providing a new target for immunotherapy of ovarian cancer. |
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