Exosomal ITGB2 Mediates Immune Evasion in Triple-Negative Breast Cancer by Suppressing Dendritic Cell Activation via TLR4
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Abstract
Background: This study investigates the role of exosomal integrin beta-2 (ITGB2) from triple-negative breast cancer (TNBC) cells in modulating immune responses, with a focus on its interaction with Toll-like receptor 4 (TLR4) in dendritic cells (DCs). This study aimed to understand how ITGB2 contributes to the immunosuppressive tumor microenvironment in TNBC.
Methods: ITGB2 expression in TNBC tissues and cell lines was analyzed using qPCR and Western blot at the Affiliated Cancer Hospital of Xinjiang Medical University between 2013 and 2015. Knockdown and overexpression models of ITGB2 were established in MDA-MB-231 cells to explore their effects on TLR4 expression in DCs. Exosomes were isolated from these cells, and DCs were co-cultured with exosomes to measure TLR4 expression and cytokine secretion using flow cytometry and ELISA.
Results: ITGB2 was overexpressed in TNBC tissues, correlating with poor prognosis. Exosomal ITGB2 from TNBC cells suppressed TLR4 expression in DCs, leading to impaired DC maturation and reduced cytokine secretion, thus promoting an immunosuppressive microenvironment.
Conclusion: Targeting the ITGB2-TLR4 axis could enhance anti-tumor immunity in TNBC. ITGB2 holds potential as a biomarker and therapeutic target, suggesting that inhibition of exosomal ITGB2 or restoration of DC function may improve therapeutic outcomes in TNBC.
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11. Zu L, He J, Zhou N, et al (2022). The Pro-file and Clinical Significance of ITGB2 Expression in Non-Small-Cell Lung Cancer. J Clin Med, 11(21):6421.
12. Wylie B, Macri C, Mintern JD, Waithman J (2019). Dendritic Cells and Cancer: From Biology to Therapeutic Interven-tion. Cancers (Basel), 11(4):521.
13. Garris CS, Arlauckas SP, Kohler RH, et al (2018). Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12. Immunity, 49(6):1148-1161.e7.
14. Shapaer T, Chen Y, Pan Y, et al (2024). Ele-vated BEAN1 expression correlates with poor prognosis, immune evasion, and chemotherapy resistance in rectal ade-nocarcinoma. Discov Oncol, 15(1):446.
15. Shahverdi M, Masoumi J, Ghorbaninezhad F, et al (2022). The modulatory role of dendritic cell-T cell cross-talk in breast cancer: Challenges and prospects. Adv Med Sci, 67(2):353-363.
16. Chen Y, Zhang B, Wang X, et al (2025). Prognostic value of preoperative modi-fied Glasgow prognostic score in pre-dicting overall survival in breast cancer patients: A retrospective cohort study. Oncol Lett, 29(4):180.
17. Carvalho FM (2023). Triple-negative breast cancer: from none to multiple therapeu-tic targets in two decades. Front Oncol, 13:1244781.
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19. Li J, Wu Z, Pan Y, et al (2024). GNL3L ex-hibits pro-tumor activities via NF-κB pathway as a poor prognostic factor in acute myeloid leukemia. J Cancer, 15(13):4072-4080.
20. Baba AB, Rah B, Bhat GR, et al (2022). Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol, 13:791272.
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23. Qian D, Li J, Huang M, Cui Q, Liu X, Sun K (2023). Dendritic cell vaccines in breast cancer: Immune modulation and immu-notherapy. Biomed Pharmacother, 162:114685.
24. Yin L, Xie S, Chen Y, et al (2021). Novel germline mutation KMT2A G3131S con-fers genetic susceptibility to familial myeloproliferative neoplasms. Ann He-matol, 100(9):2229-2240.
25. Othman N, Jamal R, Abu N (2019). Cancer-Derived Exosomes as Effectors of Key Inflammation-Related Players. Front Im-munol, 10:2103.
26. Shayimu P, Awula M, Wang CY, et al (2024). Serum nutritional predictive biomarkers and risk assessment for anastomotic leakage after laparoscopic surgery in rectal cancer patients. World J Gastrointest Surg, 16(10):3142-3154.
27. Kim HJ, Kim H, Lee JH, Hwangbo C (2023). Toll-like receptor 4 (TLR4): new insight immune and aging. Immun Ageing, 20(1):67.
28. Wu Z, Chen Y, Jiang D, et al (2024). Mito-chondrial-related drug resistance lncRNAs as prognostic biomarkers in laryngeal squamous cell carcinoma. Dis-cov Oncol, 15(1):785.
29. Papadakos SP, Arvanitakis K, Stergiou IE, et al (2023). Interplay of Extracellular Vesi-cles and TLR4 Signaling in Hepatocellu-lar Carcinoma Pathophysiology and Therapeutics. Pharmaceutics, 15(10):2460.
30. Das K, Paul S, Ghosh A, et al (2023). Extra-cellular Vesicles in Triple-Negative Breast Cancer: Immune Regulation, Bi-omarkers, and Immunotherapeutic Po-tential. Cancers (Basel), 15(19):4879.
31. Łazarczyk A, Streb J, Glajcar A, et al (2023). Dendritic Cell Subpopulations Are As-sociated with Prognostic Characteristics of Breast Cancer after Neoadjuvant Chemotherapy-An Observational Study. Int J Mol Sci, 24(21):15817.
32. Weng J, Yang J, Wang W, et al (2023). Ap-plication of microneedles combined with dendritic cell-targeted nanovaccine delivery system in percutaneous immu-notherapy for triple-negative breast cancer. Nanotechnology, 34(47):10.1088/1361-6528/ace97b.
33. Jugniot N, Dahl JJ, Paulmurugan R (2022). Immunotheranostic microbubbles (iMBs) - a modular platform for dendrit-ic cell vaccine delivery applied to breast cancer immunotherapy. J Exp Clin Can-cer Res, 41(1):299.
2. Zheng S, Zou Y, Tang Y, et al (2022). Land-scape of cancer-associated fibroblasts identifies the secreted biglycan as a pro-tumor and immunosuppressive factor in triple-negative breast cancer. Oncoim-munology, 11(1):2020984.
3. Xie J, Zheng Z, Tuo L, et al (2023). Recent advances in exosome-based immuno-therapy applied to cancer. Front Immunol, 14:1296857.
4. Xie H, Jiang Y, Xiang Y, et al (2024). Super-enhancer-driven LIF promotes the mes-enchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia. Neuro Oncol, 26(8):1438-1452.
5. Nawaz Tipu H, Raza R, Jaffar S, et al (2020). β2 Integrin Gene (ITGB2) muta-tion spectra in Pakistani families with leukocyte adhesion deficiency type 1 (LAD1). Immunobiology, 225(3):151938.
6. Wu Z, Chen Y, Yu G, Ma Y (2024). Re-search trends and hotspots in surgical treatment of recurrent nasopharyngeal carcinoma: A bibliometric analysis from 2000 to 2023. Asian J Surg, 47(6):2939-2941.
7. Zhang H, Shi Y, Ying J, et al (2023). A bib-liometric and visualized research on global trends of immune checkpoint in-hibitors related complications in mela-noma, 2011-2021. Front Endocrinol (Lau-sanne), 14:1164692.
8. Zhang F, Wu Z, Sun S, Fu Y, Chen Y, Liu J (2023). POEMS syndrome in the 21st century: A bibliometric analysis. Heliyon, 9(10):e20612.
9. Li J, Cao D, Jiang L, et al (2024). ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with re-tained hypoxia and ECM signatures. Cell Oncol (Dordr), 47(3):951-965.
10. Morrison VL, MacPherson M, Savinko T, Lek HS, Prescott A, Fagerholm SC (2013). The β2 integrin-kindlin-3 interaction is essential for T-cell homing but dispen-sable for T-cell activation in vivo. Blood, 122(8):1428-1436.
11. Zu L, He J, Zhou N, et al (2022). The Pro-file and Clinical Significance of ITGB2 Expression in Non-Small-Cell Lung Cancer. J Clin Med, 11(21):6421.
12. Wylie B, Macri C, Mintern JD, Waithman J (2019). Dendritic Cells and Cancer: From Biology to Therapeutic Interven-tion. Cancers (Basel), 11(4):521.
13. Garris CS, Arlauckas SP, Kohler RH, et al (2018). Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12. Immunity, 49(6):1148-1161.e7.
14. Shapaer T, Chen Y, Pan Y, et al (2024). Ele-vated BEAN1 expression correlates with poor prognosis, immune evasion, and chemotherapy resistance in rectal ade-nocarcinoma. Discov Oncol, 15(1):446.
15. Shahverdi M, Masoumi J, Ghorbaninezhad F, et al (2022). The modulatory role of dendritic cell-T cell cross-talk in breast cancer: Challenges and prospects. Adv Med Sci, 67(2):353-363.
16. Chen Y, Zhang B, Wang X, et al (2025). Prognostic value of preoperative modi-fied Glasgow prognostic score in pre-dicting overall survival in breast cancer patients: A retrospective cohort study. Oncol Lett, 29(4):180.
17. Carvalho FM (2023). Triple-negative breast cancer: from none to multiple therapeu-tic targets in two decades. Front Oncol, 13:1244781.
18. Laha D, Grant R, Mishra P, Nilubol N (2021). The Role of Tumor Necrosis Factor in Manipulating the Immunolog-ical Response of Tumor Microenviron-ment. Front Immunol, 12:656908.
19. Li J, Wu Z, Pan Y, et al (2024). GNL3L ex-hibits pro-tumor activities via NF-κB pathway as a poor prognostic factor in acute myeloid leukemia. J Cancer, 15(13):4072-4080.
20. Baba AB, Rah B, Bhat GR, et al (2022). Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol, 13:791272.
21. Gautam N, Ramamoorthi G, Champion N, Han HS, Czerniecki BJ (2024). Reviewing the significance of dendritic cell vac-cines in interrupting breast cancer de-velopment. Mol Aspects Med, 95:101239.
22. Doherty MR, Cheon H, Junk DJ, et al (2017). Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci U S A, 114(52):13792-13797.
23. Qian D, Li J, Huang M, Cui Q, Liu X, Sun K (2023). Dendritic cell vaccines in breast cancer: Immune modulation and immu-notherapy. Biomed Pharmacother, 162:114685.
24. Yin L, Xie S, Chen Y, et al (2021). Novel germline mutation KMT2A G3131S con-fers genetic susceptibility to familial myeloproliferative neoplasms. Ann He-matol, 100(9):2229-2240.
25. Othman N, Jamal R, Abu N (2019). Cancer-Derived Exosomes as Effectors of Key Inflammation-Related Players. Front Im-munol, 10:2103.
26. Shayimu P, Awula M, Wang CY, et al (2024). Serum nutritional predictive biomarkers and risk assessment for anastomotic leakage after laparoscopic surgery in rectal cancer patients. World J Gastrointest Surg, 16(10):3142-3154.
27. Kim HJ, Kim H, Lee JH, Hwangbo C (2023). Toll-like receptor 4 (TLR4): new insight immune and aging. Immun Ageing, 20(1):67.
28. Wu Z, Chen Y, Jiang D, et al (2024). Mito-chondrial-related drug resistance lncRNAs as prognostic biomarkers in laryngeal squamous cell carcinoma. Dis-cov Oncol, 15(1):785.
29. Papadakos SP, Arvanitakis K, Stergiou IE, et al (2023). Interplay of Extracellular Vesi-cles and TLR4 Signaling in Hepatocellu-lar Carcinoma Pathophysiology and Therapeutics. Pharmaceutics, 15(10):2460.
30. Das K, Paul S, Ghosh A, et al (2023). Extra-cellular Vesicles in Triple-Negative Breast Cancer: Immune Regulation, Bi-omarkers, and Immunotherapeutic Po-tential. Cancers (Basel), 15(19):4879.
31. Łazarczyk A, Streb J, Glajcar A, et al (2023). Dendritic Cell Subpopulations Are As-sociated with Prognostic Characteristics of Breast Cancer after Neoadjuvant Chemotherapy-An Observational Study. Int J Mol Sci, 24(21):15817.
32. Weng J, Yang J, Wang W, et al (2023). Ap-plication of microneedles combined with dendritic cell-targeted nanovaccine delivery system in percutaneous immu-notherapy for triple-negative breast cancer. Nanotechnology, 34(47):10.1088/1361-6528/ace97b.
33. Jugniot N, Dahl JJ, Paulmurugan R (2022). Immunotheranostic microbubbles (iMBs) - a modular platform for dendrit-ic cell vaccine delivery applied to breast cancer immunotherapy. J Exp Clin Can-cer Res, 41(1):299.
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| Issue | Vol 54 No 6 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Triple-negative breast cancer Dendritic cell Exosome | ||
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How to Cite
1.
Paierhati P, Ma B, Abudukeremu M. Exosomal ITGB2 Mediates Immune Evasion in Triple-Negative Breast Cancer by Suppressing Dendritic Cell Activation via TLR4. Iran J Public Health. 2025;54(6):1252-1262.
