Inhibitory Immune Checkpoints in OvarianCancer Development

Background: Inhibitory immune checkpoints (IICs) are implicatedin developing an immunosuppressive tumor microenvironmentin solid cancers. IICs shield malignant cells fromanti-tumoral immune responses, facilitating their growth andmetastasis. Despite the recent advances in our understandingof cancer biology and immunity, ovarian cancer (OC) carries apoor prognosis. Given the remarkable advances in next-generationsequencing, we studied the IICs in OC development andtheir significance in platinum-based chemotherapy resistanceand the survival of OC patients.Materials and Methods: GSE۵۴۳۸۸ and GSE۱۱۴۲۰۶ were accessedto study the significance of IIC molecules in OC tissuesand chemotherapy resistance, respectively. The limma packagewas used to identify the differential expressed genes (DEGs)using R software (version ۴.۰.۳); |Log۲Fold change| > ۱.۴ adjustedp-value < ۰.۰۱ were the criteria for identifying DEGs.The TCGA-OC was accessed to study the prognostic values ofidentified upregulated ICCs and their correlations. The associationsbetween these molecules and immune cell infiltrationwere also studied in OC samples. The total RNA, complementarycDNA, and quantitative reverse transcription PCR (RT-qPCR)were performed on HOSEpiC, SKOV۳, and A۲۷۸۰ cells tostudy the mRNA expression of ILDR۲ and NT۵E.Results: The expression levels of ILDR۲ and NT۵E were significantlyupregulated in OC tissues. Besides, the TCGA-OCindicated a significant positive correlation between ILDR۲ andNT۵E expression in OC tissues (R= ۰.۲۱, P-value = ۰.۰۰۰۲).NT۵E upregulation was associated with inferior disease-freeinterval, and ILDR۲ increased expression was associated withpoor overall survival and disease-specific survival of patients.Although ILDR۲ expression was not significantly altered inplatinum-resistant OCs, NT۵E expression was significantlyupregulated in platinum-resistant OCs compared to platinumsensitiveones. Also, a positive correlation between NT۵E andinduced regulatory T-cells and a negative correlation with naïveCD۸+ T-cells were noted (R= ۰.۳۷, P-value = ۳.۳۷۹۲۶E-۱۰, andR= -۰.۲۷, P-value = ۶.۹۷۱۴۳E-۰۶, respectively). Furthermore,ILDR۲ with memory T-cells had a significant negative correlation(R = -۰.۲ and P-value = ۰.۰۰۱). Our results have shown thatthe expression levels of ILDR۲ and NT۵E are upregulated inovarian cancer cells compared to non-tumoral ovarian surfaceepithelial cells.Conclusion: ILDR۲ and NT۵E are upregulated in OC development,and their upregulation is associated with poor prognosisand immunosuppression. Besides contributing to immunosup pression, NT۵E is involved in platinum-based chemotherapyresistance.

کلیدواژه ها:

Ovarian cancer ، Immune checkpoints ، Immunotherapy ، chemotherapy