{"title":"EGCG remodels the TGF-β cervical cancer micro-environment towards immune responsiveness","authors":"Jayapradha Gnanagurusamy , Rajalakshmi Sabanayagam , Sneha Krishnamoorthy , Vidya Balasubramanian , Sridhar Muthusami","doi":"10.1016/j.cellimm.2025.105027","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Exploring the role of immune modulators alongside TGF-β in cervical cancer (CC) and PBMCs may improve the understanding of targeted treatment strategies.</div></div><div><h3>Methods</h3><div>We analyzed expression, overall survival (OS), correlation and tumor infiltration of PD-L1, CD55 and CD46, as well as immune cell fractions in CC patients using OncoDB, TIMER 2.0 and TCIA. RT-PCR and western blotting was performed to assess PD-L1, CD55 and CD46 expression. Viability, mitored, apoptosis and MMP-2 were evaluated in CC cells co-cultured with PBMCs. Morphology, crystal violet staining, ROS and MMP-2 were examined in SiHa spheroids.</div></div><div><h3>Results</h3><div>PD-L1 was upregulated, CD55 was significantly increased and CD46 showed no significant difference in HPV16 positive compared with HPV negative individuals. Elevated PD-L1, CD55 and CD46 were associated with reduced OS in HPV16 positive individuals. PD-L1 and CD55 showed moderate positive and negative correlation with TGF-β, respectively, whereas CD46 correlation was negligible. Immune fractions including M1 macrophages (31 %), M2 macrophages (17 %), CD8 T cells (21 %), NK cells (10 %), were linked to reduced OS. TGF-β, PD-L1 and CD46 infiltration were positively corelated with CD8+ T cells. In CC cells, TGF-β stimulation increased PD-L1, while decreasing CD55 and CD46, reducing viability, metabolic activity and inducing apoptosis in HPV (+) co-cultures. EGCG treatment under TGF-β, reduced PD-L1, CD55 and CD46 expression, decreased viability, metabolic activity and MMP-2 secretion, while inducing apoptosis in SiHa co-culture. In 3D spheroids, EGCG inhibited proliferation and MMP-2 activity while increasing ROS production.</div></div><div><h3>Conclusion</h3><div>EGCG, by targeting TGF-β and modulating PD-L1 and mCRPs, represents a promising candidate for immunotherapeutic development in CC.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"418 ","pages":"Article 105027"},"PeriodicalIF":2.9000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0008874925001133","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Exploring the role of immune modulators alongside TGF-β in cervical cancer (CC) and PBMCs may improve the understanding of targeted treatment strategies.
Methods
We analyzed expression, overall survival (OS), correlation and tumor infiltration of PD-L1, CD55 and CD46, as well as immune cell fractions in CC patients using OncoDB, TIMER 2.0 and TCIA. RT-PCR and western blotting was performed to assess PD-L1, CD55 and CD46 expression. Viability, mitored, apoptosis and MMP-2 were evaluated in CC cells co-cultured with PBMCs. Morphology, crystal violet staining, ROS and MMP-2 were examined in SiHa spheroids.
Results
PD-L1 was upregulated, CD55 was significantly increased and CD46 showed no significant difference in HPV16 positive compared with HPV negative individuals. Elevated PD-L1, CD55 and CD46 were associated with reduced OS in HPV16 positive individuals. PD-L1 and CD55 showed moderate positive and negative correlation with TGF-β, respectively, whereas CD46 correlation was negligible. Immune fractions including M1 macrophages (31 %), M2 macrophages (17 %), CD8 T cells (21 %), NK cells (10 %), were linked to reduced OS. TGF-β, PD-L1 and CD46 infiltration were positively corelated with CD8+ T cells. In CC cells, TGF-β stimulation increased PD-L1, while decreasing CD55 and CD46, reducing viability, metabolic activity and inducing apoptosis in HPV (+) co-cultures. EGCG treatment under TGF-β, reduced PD-L1, CD55 and CD46 expression, decreased viability, metabolic activity and MMP-2 secretion, while inducing apoptosis in SiHa co-culture. In 3D spheroids, EGCG inhibited proliferation and MMP-2 activity while increasing ROS production.
Conclusion
EGCG, by targeting TGF-β and modulating PD-L1 and mCRPs, represents a promising candidate for immunotherapeutic development in CC.
期刊介绍:
Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered.
Research Areas include:
• Antigen receptor sites
• Autoimmunity
• Delayed-type hypersensitivity or cellular immunity
• Immunologic deficiency states and their reconstitution
• Immunologic surveillance and tumor immunity
• Immunomodulation
• Immunotherapy
• Lymphokines and cytokines
• Nonantibody immunity
• Parasite immunology
• Resistance to intracellular microbial and viral infection
• Thymus and lymphocyte immunobiology
• Transplantation immunology
• Tumor immunity.