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2000
Volume 20, Issue 5
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Ovarian cancer is one of the most common gynecological malignancies globally, and immunotherapy has emerged as a promising treatment strategy in recent years. However, the effectiveness of immunotherapy is often limited by immune escape mechanisms.

Objective

To unravel the immune response mechanisms in ovarian cancer, this study aimed to employ integrated Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and single-cell sequencing analysis to systematically investigate immune infiltration-related molecular features in ovarian cancer patients and experimentally validate the molecular mechanisms of the immune response. This research may provide a new theoretical foundation and treatment strategy for immune-based therapies in ovarian cancer.

Methods

Relevant ovarian cancer datasets were collected from public databases. The ConsensusClusterPlus and ggplot2 R packages were used to perform dimensionality reduction and clustering analysis of immune infiltration-related genes. Various algorithms were employed to select the best ovarian cancer prognostic model with OC consistency. The prognostic value of angiogenesis and immune-related gene expression was evaluated through Kaplan-Meier survival analysis, and the impact of immune infiltration on immune function in ovarian cancer patients was assessed. Functional pathways were identified using the Gene Set Enrichment Analysis (GSEA) method, and the infiltration abundance of immune and stromal components was inferred using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. The influence of angiogenesis on the cellular level of Ovarian Cancer (OC) was explored in single-cell sequencing data, followed by cell experiments for further validation. The effect of the angiogenesis model on OC was evaluated through the above-mentioned research and experiments, aiming to investigate the mechanism of targeted therapy strategies in ovarian cancer.

Results

Immune-related data were collected from ovarian cancer patients in this study. Through WGCNA analysis, the MEturquoise module was identified, and a total of 1018 hub genes were determined. A prediction model was constructed using machine learning, with CoxBoost+StepCox selected as the best model, leading to the identification of 10 genes associated with ovarian cancer. Patients with high AIDPS had shorter survival time, and GSEA analysis revealed enrichment in immune-related pathways. Single-sample gene set enrichment analysis demonstrated increased immune cell infiltration and malignant stromal changes in the high AIDPS group. Results from cell experiments showed that silencing RPL31 inhibited the proliferation and migration of ovarian cancer cells while enhancing immune response capability.

Conclusion

AIDPS holds significant clinical significance in Ovarian Cancer (OC) with poor prognosis observed in patients with high AIDPS. These patients exhibit more significant genomic variations, denser immune cell infiltration, and greater tolerance toward immune therapy. Importantly, inhibiting the expression of RPL31, a key component of AIDPS, can significantly suppress the proliferation, migration, and invasive properties of ovarian cancer cells, while stimulating the cytotoxicity of effector T cells and promoting immune response, thus slowing down the progression of ovarian cancer.

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2025-12-05
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References

  1. HolschneiderC.H. BerekJ.S. Ovarian cancer: Epidemiology, biology, and prognostic factors.Semin. Surg. Oncol.200019131010.1002/1098‑2388(200007/08)19:1<3::AID‑SSU2>3.0.CO;2‑S10883018
    [Google Scholar]
  2. SiegelR.L. MillerK.D. JemalA. Cancer statistics, 2020.CA Cancer J. Clin.202070173010.3322/caac.2159031912902
    [Google Scholar]
  3. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
    [Google Scholar]
  4. TorreL.A. TrabertB. DeSantisC.E. MillerK.D. SamimiG. RunowiczC.D. GaudetM.M. JemalA. SiegelR.L. Ovarian cancer statistics, 2018.CA Cancer J. Clin.201868428429610.3322/caac.2145629809280
    [Google Scholar]
  5. CaoW. ChenH.D. YuY.W. LiN. ChenW.Q. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020.Chin. Med. J. (Engl.)2021134778379110.1097/CM9.000000000000147433734139
    [Google Scholar]
  6. OhsugaT. YamaguchiK. KidoA. MurakamiR. AbikoK. HamanishiJ. KondohE. BabaT. KonishiI. MatsumuraN. Distinct preoperative clinical features predict four histopathological subtypes of high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum.BMC Cancer201717158010.1186/s12885‑017‑3573‑128851311
    [Google Scholar]
  7. PratJ. Staging classification for cancer of the ovary, fallopian tube, and peritoneum.Int. J. Gynaecol. Obstet.201412411510.1016/j.ijgo.2013.10.00124219974
    [Google Scholar]
  8. ZhuY.T. WuS.Y. YangS. YingJ. TianL. XuH.L. ZhangH.P. YaoH. ZhangW.Y. JinQ.Q. YangY.T. JiangX.Y. ZhangN. YaoS. ZhouS.G. ChenG. Identification and validation of a novel anoikis-related signature for predicting prognosis and immune landscape in ovarian serous cystadenocarcinoma.Heliyon202398e1870810.1016/j.heliyon.2023.e1870837554782
    [Google Scholar]
  9. OjaveeS.E. DarrousL. PatxotM. LällK. FischerK. MägiR. KutalikZ. RobinsonM.R. Genetic insights into the age-specific biological mechanisms governing human ovarian aging.Am. J. Hum. Genet.202311091549156310.1016/j.ajhg.2023.07.00637543033
    [Google Scholar]
  10. PhungM.T. LeeA.W. McLeanK. Anton-CulverH. BanderaE.V. CarneyM.E. Chang-ClaudeJ. CramerD.W. DohertyJ.A. FortnerR.T. GoodmanM.T. HarrisH.R. JensenA. ModugnoF. MoysichK.B. PharoahP.D.P. QinB. TerryK.L. TitusL.J. WebbP.M. WuA.H. ZeinomarN. ZiogasA. BerchuckA. ChoK.R. HanleyG.E. MezaR. MukherjeeB. PikeM.C. PearceC.L. TrabertB. A framework for assessing interactions for risk stratification models: The example of ovarian cancer.J. Natl. Cancer Inst.2023115111420142610.1093/jnci/djad13737436712
    [Google Scholar]
  11. PowlesT. ParkS.H. VoogE. CasertaC. ValderramaB.P. GurneyH. KalofonosH. RadulovićS. DemeyW. UllénA. LoriotY. SridharS.S. TsuchiyaN. KopyltsovE. SternbergC.N. BellmuntJ. Aragon-ChingJ.B. PetrylakD.P. LaliberteR. WangJ. HuangB. DavisC. FowstC. CostaN. Blake-HaskinsJ.A. di PietroA. GrivasP. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.N. Engl. J. Med.2020383131218123010.1056/NEJMoa200278832945632
    [Google Scholar]
  12. OrrB. EdwardsR.P. Diagnosis and treatment of ovarian cancer.Hematol. Oncol. Clin. North Am.201832694396410.1016/j.hoc.2018.07.01030390767
    [Google Scholar]
  13. XiaoY. BiM. GuoH. LiM. Multi-omics approaches for biomarker discovery in early ovarian cancer diagnosis.EBioMedicine20227910400110.1016/j.ebiom.2022.10400135439677
    [Google Scholar]
  14. WangH. LiuJ. YangJ. WangZ. ZhangZ. PengJ. WangY. HongL. A novel tumor mutational burden-based risk model predicts prognosis and correlates with immune infiltration in ovarian cancer.Front. Immunol.20221394338910.3389/fimmu.2022.94338936003381
    [Google Scholar]
  15. LaumontC.M. WoutersM.C.A. SmazynskiJ. GiercN.S. ChavezE.A. ChongL.C. ThorntonS. MilneK. WebbJ.R. SteidlC. NelsonB.H. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer.Clin. Cancer Res.202127144089410010.1158/1078‑0432.CCR‑20‑439433963000
    [Google Scholar]
  16. SantoiemmaP.P. PowellD.J.Jr Tumor infiltrating lymphocytes in ovarian cancer.Cancer Biol. Ther.201516680782010.1080/15384047.2015.104096025894333
    [Google Scholar]
  17. LiuS. JinK. HuiY. FuJ. JieC. FengS. ReismanD. WangQ. FanD. SukumarS. ChenH. HOXB7 promotes malignant progression by activating the TGFβ signaling pathway.Cancer Res.201575470971910.1158/0008‑5472.CAN‑14‑310025542862
    [Google Scholar]
  18. TommasiniD. FogelB.L. multiWGCNA: An R package for deep mining gene co-expression networks in multi-trait expression data.BMC Bioinformatics202324111510.1186/s12859‑023‑05233‑z36964502
    [Google Scholar]
  19. LangfelderP. HorvathS. WGCNA: An R package for weighted correlation network analysis.BMC Bioinformatics20089155910.1186/1471‑2105‑9‑55919114008
    [Google Scholar]
  20. SchusterH. RoehleK. Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers.US Patent 20240034769A12024
  21. HuangW. WuY. LuoN. ShuaiX. GuoJ. WangC. YangF. LiuL. LiuS. ChengZ. Identification of TRPM2 as a prognostic factor correlated with immune infiltration in ovarian cancer.J. Ovarian Res.202316116910.1186/s13048‑023‑01225‑y37608401
    [Google Scholar]
  22. MuaibatiM. AbuduyilimuA. ZhangT. DaiY. LiR. HuangF. LiK. TongQ. HuangX. ZhuangL. Efficacy of immune checkpoint inhibitor monotherapy or combined with other small molecule-targeted agents in ovarian cancer.Expert Rev. Mol. Med.202325e610.1017/erm.2023.336691778
    [Google Scholar]
  23. GuoW. ZhengY. XuB. MaF. LiC. ZhangX. WangY. ChangX. Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors.OncoTargets Ther.2017101475148510.2147/OTT.S9238928331341
    [Google Scholar]
  24. LiuL. ZhangZ. ZhangG. WangT. MaY. GuoW. Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib.J. Transl. Med.202018135710.1186/s12967‑020‑02528‑032951601
    [Google Scholar]
  25. VlamingM. BilemjianV. FreileJ.Á. MeloV. PlatA. HulsG. NijmanH.W. de BruynM. BremerE. Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival.Front. Immunol.202213103174610.3389/fimmu.2022.103174636341460
    [Google Scholar]
  26. GuC. XiongX. LiuW. Prognostic Significance of the CXCLs and Its Impact on the Immune Microenvironment in Ovarian Cancer.Dis. Markers2023202311110.1155/2023/522365736798787
    [Google Scholar]
  27. HouY. QiaoS. LiM. HanX. WeiX. PangY. MaoH. The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit.Front. Genet.202313109064010.3389/fgene.2022.109064036704336
    [Google Scholar]
  28. WamaithaS.E. NieX. PandolfiE.C. WangX. YangY. StukenborgJ.B. CairnsB.R. GuoJ. ClarkA.T. Single-cell analysis of the developing human ovary defines distinct insights into ovarian somatic and germline progenitors.Dev. Cell2023582020972111.e310.1016/j.devcel.2023.07.01437582368
    [Google Scholar]
  29. TangP.W. FrisbieL. HempelN. CoffmanL. Insights into the tumor-stromal-immune cell metabolism cross talk in ovarian cancer.Am. J. Physiol. Cell Physiol.20233253C731C74910.1152/ajpcell.00588.2022
    [Google Scholar]
  30. SchabA.M. GreenwadeM.M. StockE. LomonosovaE. ChoK. GritherW.R. NoiaH. WilkeD. MullenM.M. HagemannA.R. HagemannI.S. ThakerP.H. KurokiL.M. McCourtC.K. KhabeleD. PowellM.A. MutchD.G. ZhaoP. ShriverL.P. PattiG.J. LongmoreG.D. FuhK.C. Stromal DDR2 promotes ovarian cancer metastasis through regulation of metabolism and secretion of extracellular matrix proteins.Mol. Cancer Res.202321111234124810.1158/1541‑7786.MCR‑23‑034737527178
    [Google Scholar]
  31. Koren CarmiY. KhamaisiH. AdawiR. NoymanE. GopasJ. MahajnaJ. Secreted soluble factors from tumor-activated mesenchymal stromal cells confer platinum chemoresistance to ovarian cancer cells.Int. J. Mol. Sci.2023249773010.3390/ijms2409773037175439
    [Google Scholar]
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