Abstract
Purpose
Forkhead Box Protein 3 (FoxP3) is known as a key mediator in the immunosuppressive function of regulatory T-cells (Tregs). The aim of our study was to investigate whether FoxP3-positive Tregs have the potential to act as an independent predictor in progression as well as in regression of cervical intraepithelial neoplasia, especially in patients with intermediate cervical intraepithelial neoplasia (CIN II).
Methods
Nuclear FoxP3 expression was immunohistochemically analysed in 169 patient samples (CIN I, CIN II with regressive course, CIN II with progressive course, CIN III). The median numbers were calculated for each slide and correlated with the histological CIN grade. Statistical analysis was performed by SPSS 26 (Mann–Whitney U test, Spearman’s rank correlation).
Results
An increased FoxP3 expression in CIN II with progression could be detected in comparison to CIN II with regression (p = 0.003). Total FoxP3 expression (epithelium and dysplasia-connected stroma) was higher in more advanced CIN grades (p < 0.001 for CIN I vs. CIN II; p = 0.227 for CIN II vs. CIN III). A positive correlation could be detected between FoxP3-positive cells in epithelium and total FoxP3 expression (Spearman’s Rho: 0,565; p < 0.01).
Conclusion
Expression of FoxP3 could be a helpful predictive factor to assess the risks of CIN II progression. As a prognosticator for regression and progression in cervical intraepithelial lesions it might thereby help in the decision process regarding surgical treatment vs. watchful waiting strategy to prevent conisation-associated risks for patients in child-bearing age. In addition, the findings support the potential of Tregs as a target for immune therapy in cervical cancer patients.
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Availability of data and materials
The datasets generated and analysed during the current study are available from the correspondent author on reasonable request.
Code availability
Not applicable.
Abbreviations
- CIN:
-
Cervical intraepithelial neoplasia
- CTLA4:
-
Cytotoxic T-lymphocyte-associated protein 4
- Fig.:
-
Figure
- FoxP3:
-
Forkhead box protein 3
- GITR:
-
Glucocorticoid-induzierter TNF-Rezeptor
- HER2:
-
Human epidermal growth factor receptor 2
- IL:
-
Interleukin
- LAG3:
-
Lymphocyte Activating 3
- PD-L1:
-
Programmed death ligand 1
- SKP2:
-
S-Phase Kinase Associated Protein 2
- Smad2/3:
-
MAD (Mothers against decapentaplegic)/Sma (small body size)
- TCR:
-
T-cell receptor
- TGF:
-
Transforming growth factor
- TLR8:
-
Toll-like receptor 8
- Treg:
-
Regulatory T-cell
- VEGF:
-
Vascular endothelial growth factor
References
Adurthi S, Krishna S, Mukherjee G, Bafna UD, Devi U, Jayshree RS (2008) Regulatory T cells in a spectrum of HPV-induced cervical lesions: cervicitis, cervical intraepithelial neoplasia and squamous cell carcinoma. Am J Reprod Immunol 60(1):55–65. https://doi.org/10.1111/j.1600-0897.2008.00590.x
Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, Prendiville W, Paraskevaidis E (2008) Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ (clin Res Ed) 337:a1284. https://doi.org/10.1136/bmj.a1284
Arends MJ, Buckley CH, Wells M (1998) Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol 51(2):96–103. https://doi.org/10.1136/jcp.51.2.96
Bashaw AA, Teoh SM, Tuong ZK, Leggatt GR, Frazer IH, Chandra J (2019) HPV16 E7-Driven Epithelial Hyperplasia Promotes Impaired Antigen Presentation and Regulatory T-Cell Development. J Invest Dermatol 139(12):2467-2476.e2463. https://doi.org/10.1016/j.jid.2019.03.1162
Bonin CM, Padovani CTJ, da Costa IP, Ávila LS, Ferreira AMT, Fernandes CES, Dos Santos AR, Tozetti IA (2019) Detection of regulatory T cell phenotypic markers and cytokines in patients with human papillomavirus infection. J Med Virol 91(2):317–325. https://doi.org/10.1002/jmv.25312
Boyer SN, Wazer DE, Band V (1996) E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 56(20):4620–4624. https://cancerres.aacrjournals.org/content/canres/56/20/4620.full.pdf
Chellappan S, Kraus VB, Kroger B, Munger K, Howley PM, Phelps WC, Nevins JR (1992) Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA 89(10):4549–4553. https://doi.org/10.1073/pnas.89.10.4549
Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A (2019) Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 37(17):1470–1478. https://doi.org/10.1200/jco.18.01265
Colamatteo A, Carbone F, Bruzzaniti S, Galgani M, Fusco C, Maniscalco GT, Di Rella F, de Candia P, De Rosa V (2020) Molecular mechanisms controlling Foxp3 expression in health and autoimmunity: from epigenetic to post-translational regulation. Front Immunol 10:3136–3136. https://doi.org/10.3389/fimmu.2019.03136
Curiel TJ (2008) Regulatory T cells and treatment of cancer. Curr Opin Immunol 20(2):241–246. https://doi.org/10.1016/j.coi.2008.04.008
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. https://doi.org/10.1038/nm1093
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC (2012) The lower anogenital squamous terminology standardization project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 16(3):205–242. https://doi.org/10.1097/LGT.0b013e31825c31dd
De Jong RA et al (2009) Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 114(1):105–110
Demir L, Yigit S, Ellidokuz H, Erten C, Somali I, Kucukzeybek Y, Alacacioglu A, Cokmert S, Can A, Akyol M, Dirican A, Bayoglu V, Sari AA, Tarhan MO (2013) Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs. Clin Exp Metastasis 30(8):1047–1062. https://doi.org/10.1007/s10585-013-9602-9
Deng L, Zhang H, Luan Y, Zhang J, Xing Q, Dong S, Wu X, Liu M, Wang S (2010) Accumulation of foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin Cancer Res 16(16):4105–4112. https://doi.org/10.1158/1078-0432.Ccr-10-1073
Douglass S, Meeson AP, Overbeck-Zubrzycka D, Brain JG, Bennett MR, Lamb CA, Lennard TW, Browell D, Ali S, Kirby JA (2014) Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12. J Pathol 234(1):74–85. https://doi.org/10.1002/path.4381
Fischer L, Heinemann V (2020) Checkpoint-Inhibitoren bei Plattenepithelkarzinomen - Im Fokus: HNO-, Zervix- und Analkarzinome. Trillium Krebsmedizin, 02
Frenel JS, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, van Brummelen EMJ, Rugo HS, Thomas S, Saraf S, Rangwala R, Varga A (2017) Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol 35(36):4035–4041. https://doi.org/10.1200/jco.2017.74.5471
Fu Q, Chen N, Ge C, Li R, Li Z, Zeng B, Li C, Wang Y, Xue Y, Song X, Li H, Li G (2019) Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncoimmunology 8(7):1593806–1593806. https://doi.org/10.1080/2162402X.2019.1593806
Gupta S, Takhar PPS, Degenkolbe R, Heng Koh C, Zimmermann H, Maolin Yang C, Guan Sim K, I-Hong Hsu S, Bernard H-U (2003) The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br 1. Virology 317(1):155–164. https://doi.org/10.1016/j.virol.2003.08.008
Hatzioannou A, Banos A, Sakelaropoulos T, Fedonidis C, Vidali MS, Köhne M, Händler K, Boon L, Henriques A, Koliaraki V, Georgiadis P, Zoidakis J, Termentzi A, Beyer M, Chavakis T, Boumpas D, Tsirigos A, Verginis P (2020) An intrinsic role of IL-33 in T(reg) cell-mediated tumor immunoevasion. Nat Immunol 21(1):75–85. https://doi.org/10.1038/s41590-019-0555-2
Hinz S (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Can Res 67:8344–8350
Horn T, Laus J, Seitz AK, Maurer T, Schmid SC, Wolf P, Haller B, Winkler M, Retz M, Nawroth R, Gschwend JE, Kübler HR, Slotta-Huspenina J (2016) The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer. World J Urol 34(2):181–187. https://doi.org/10.1007/s00345-015-1615-3
Jang TJ (2008) Prevalence of Foxp3 positive T regulatory cells is increased during progression of cutaneous squamous tumors. Yonsei Med J 49(6):942–948. https://doi.org/10.3349/ymj.2008.49.6.942
Jørgensen N, Persson G, Hviid TVF (2019) The tolerogenic function of regulatory T cells in pregnancy and cancer. Front Immunol 10:911. https://doi.org/10.3389/fimmu.2019.00911
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, Cervantes A, de Olza MO, Marabelle A, Hodi FS, Ahn MJ, Emens LA, Barlesi F, Hamid O, Calvo E, McDermott D, Soliman H, Rhee I, Lin R, Pourmohamad T, Suchomel J, Tsuhako A, Morrissey K, Mahrus S, Morley R, Pirzkall A, Davis SL (2019) Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin Cancer Res 25(11):3220–3228. https://doi.org/10.1158/1078-0432.Ccr-18-2740
Knutson KL, Maurer MJ, Preston CC, Moysich KB, Goergen K, Hawthorne KM, Cunningham JM, Odunsi K, Hartmann LC, Kalli KR, Oberg AL, Goode EL (2015) Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer. Cancer Immunol Immunother 64(12):1495–1504. https://doi.org/10.1007/s00262-015-1753-x
Kojima S, Kawana K, Tomio K, Yamashita A, Taguchi A, Miura S, Adachi K, Nagamatsu T, Nagasaka K, Matsumoto Y, Arimoto T, Oda K, Wada-Hiraike O, Yano T, Taketani Y, Fujii T, Schust DJ, Kozuma S (2013) The prevalence of cervical regulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inversely with spontaneous regression of CIN. Am J Reprod Immunol 69(2):134–141. https://doi.org/10.1111/aji.12030
Kolben TM, Kraft F, Kolben T, Goess C, Semmlinger A, Dannecker C, Schmoeckel E, Mayr D, Sommer NN, Mahner S, Jeschke U (2017) Expression of Sialyl Lewis a, Sialyl Lewis x, Lewis y, Gal-3, Gal-7, STMN1 and p16 in cervical dysplasia. Future Oncol 13(2):145–157. https://doi.org/10.2217/fon-2016-0259
Kolben TM, Etzel LT, Bergauer F, Hagemann I, Hillemanns P, Repper M, Kaufmann AM, Sotlar K, Kolben T, Helms H-J, Gallwas J, Mahner S, Dannecker C (2019) A randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients. J Gynecol Oncol. https://doi.org/10.3802/jgo.2019.30.e42
Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S (2009) Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 106(6):1903–1908. https://doi.org/10.1073/pnas.0811556106
Kyrgiou M, Athanasiou A, Paraskevaidi M, Mitra A, Kalliala I, Martin-Hirsch P, Arbyn M, Bennett P, Paraskevaidis E (2016) Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ (clin Res Ed) 354:i3633–i3633. https://doi.org/10.1136/bmj.i3633
Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, Sundström K, Dillner J, Sparén P (2020) HPV vaccination and the risk of invasive cervical cancer. N Engl J Med 383(14):1340–1348. https://doi.org/10.1056/NEJMoa1917338
Li X, Gao Y, Li J, Zhang K, Han J, Li W, Hao Q, Zhang W, Wang S, Zeng C, Zhang W, Zhang Y, Li M, Zhang C (2018) FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer. Cell Death Dis 9(7):744–744. https://doi.org/10.1038/s41419-018-0790-8
Loddenkemper C, Hoffmann C, Stanke J, Nagorsen D, Baron U, Olek S, Huehn J, Ritz J-P, Stein H, Kaufmann AM, Schneider A, Cichon G (2009) Regulatory (FOXP3+) T cells as target for immune therapy of cervical intraepithelial neoplasia and cervical cancer. Cancer Sci 100(6):1112–1117. https://doi.org/10.1111/j.1349-7006.2009.01153.x
Miyara M, Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13(3):108–116. https://doi.org/10.1016/j.molmed.2007.01.003
Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, López-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN (2019) Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II checkmate 358 trial. J Clin Oncol 37(31):2825–2834. https://doi.org/10.1200/jco.19.00739
NCCN-Guidelines® (2020) NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer. Retrieved January 14
Ohue Y, Nishikawa H (2019) Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci 110(7):2080–2089. https://doi.org/10.1111/cas.14069
Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Can Res 59:3128–3133
Paraskevaidis E et al (1992) A population-based study of microinvasive disease of the cervix–a colposcopic and cytologic analysis. Gynecol Oncol 45(1):9–12
Peng GL, Li L, Guo YW, Yu P, Yin XJ, Wang S, Liu CP (2019) CD8(+) cytotoxic and FoxP3(+) regulatory T lymphocytes serve as prognostic factors in breast cancer. Am J Transl Res 11(8):5039–5053
Perrone G, Ruffini PA, Catalano V, Spino C, Santini D, Muretto P, Spoto C, Zingaretti C, Sisti V, Alessandroni P, Giordani P, Cicetti A, D’Emidio S, Morini S, Ruzzo A, Magnani M, Tonini G, Rabitti C, Graziano F (2008) Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 44(13):1875–1882. https://doi.org/10.1016/j.ejca.2008.05.017
Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241(1):260–268. https://doi.org/10.1111/j.1600-065X.2011.01018.x
Sato E et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63(6):1129–1136. https://doi.org/10.1016/0092-8674(90)90409-8
Schiffman M, Wentzensen N (2013) Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. CEBP Focus 22(4):553–560. https://doi.org/10.1158/1055-9965.EPI-12-1406
Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201(5):723–735. https://doi.org/10.1084/jem.20041982
Shi J-Y, Ma L-J, Zhang J-W, Duan M, Ding Z-B, Yang L-X, Cao Y, Zhou J, Fan J, Zhang X, Zhao Y-J, Wang X-Y, Gao Q (2017) FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway. BMC Cancer 17(1):648–648. https://doi.org/10.1186/s12885-017-3633-6
Silver MI, Gage JC, Schiffman M, Fetterman B, Poitras NE, Lorey T, Cheung LC, Katki HA, Locke A, Kinney WK, Castle PE (2018) Clinical outcomes after conservative management of cervical intraepithelial neoplasia grade 2 (CIN2) in women ages 21–39 years. Cancer Prev Res 11(3):165–170. https://doi.org/10.1158/1940-6207.CAPR-17-0293
Tainio K, Athanasiou A, Tikkinen KAO, Aaltonen R, Cárdenas J, Hernándes Glazer-Livson S, Jakobsson M, Joronen K, Kiviharju M, Louvanto K, Oksjoki S, Tähtinen R, Virtanen S, Nieminen P, Kyrgiou M, Kalliala I (2018) Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. The BMJ 360:k499. https://doi.org/10.1136/bmj.k499
Tang J, Yang Z, Wang Z, Li Z, Li H, Yin J, Deng M, Zhu W, Zeng C (2017) Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World J Surg Oncol 15(1):173–173. https://doi.org/10.1186/s12957-017-1221-5
Vacchelli E, Semeraro M, Adam J, Dartigues P, Zitvogel L, Kroemer G (2016) Immunosurveillance in esophageal carcinoma: the decisive impact of regulatory T cells. Oncoimmunology 5(2):e1064581. https://doi.org/10.1080/2162402x.2015.1064581
Visser J, Nijman HW, Hoogenboom BN, Jager P, van Baarle D, Schuuring E, Abdulahad W, Miedema F, van der Zee AG, Daemen T (2007) Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia. Clin Exp Immunol 150(2):199–209. https://doi.org/10.1111/j.1365-2249.2007.03468.x
Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJF, Peto J, Meijer CJLM, Muñoz N (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189(1):12–19. https://doi.org/10.1002/(sici)1096-9896(199909)189:1<12::Aid-path431>3.0.Co;2-f
Wang L, Liu R, Ribick M, Zheng P, Liu Y (2010) FOXP3 as an X-linked tumor suppressor. Discov Med 10(53):322–328. https://pubmed.ncbi.nlm.nih.gov/21034673. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500105/
Wilkinson TM, Sykes PH, Simcock B, Petrich S (2015) Recurrence of high-grade cervical abnormalities following conservative management of cervical intraepithelial neoplasia grade 2. Am J Obstet Gynecol 212(6):769.e761–767. https://doi.org/10.1016/j.ajog.2015.01.010
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DAA (2009) The development and function of regulatory T cells. Cell Mol Life Sci CMLS 66(16):2603–2622. https://doi.org/10.1007/s00018-009-0026-2
WorldHealthOrganization (2020) World Health Assembly adopts global strategy to accelerate cervical cancer elimination. Retrieved 26 Oct 2020 from https://www.who.int/news/item/19-08-2020-world-health-assembly-adopts-global-strategy-to-accelerate-cervical-cancer-elimination
Wu L, Yi B, Wei S, Rao D, He Y, Naik G, Bae S, Liu XM, Yang W-H, Sonpavde G, Liu R, Wang L (2019) Loss of FOXP3 and TSC1 accelerates prostate cancer progression through synergistic transcriptional and posttranslational regulation of c-MYC. Cancer Res 79(7):1413–1425. https://doi.org/10.1158/0008-5472.CAN-18-2049
Xu R, Wu M, Liu S, Shang W, Li R, Xu J, Huang L, Wang F (2021) Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4(+) Treg cells in ovarian cancer cells microenvironment. Cell Death Dis 12(1):22. https://doi.org/10.1038/s41419-020-03272-5
Yang H, Ye S, Goswami S, Li T, Wu J, Cao C, Ma J, Lu B, Pei X, Chen Y, Yu J, Xu H, Qiu L, Afridi S, Xiang L, Zhang X (2020) Highly immunosuppressive HLADR(hi) regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma. Int J Cancer 146(7):1993–2006. https://doi.org/10.1002/ijc.32782
Yano H, Andrews LP, Workman CJ, Vignali DAA (2019) Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity. Immunology 157(3):232–247. https://doi.org/10.1111/imm.13067
Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H, Fu Y-X (2005) Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201(5):779–791. https://doi.org/10.1084/jem.20041684
Zeng C, Yao Y, Jie W, Zhang M, Hu X, Zhao Y, Wang S, Yin J, Song Y (2013) Up-regulation of Foxp3 participates in progression of cervical cancer. Cancer Immunol Immunother 62(3):481–487. https://doi.org/10.1007/s00262-012-1348-8
Zhang T, Jiao J, Jiao X, Zhao L, Tian X, Zhang Q, Ma D, Cui B (2017) Aberrant frequency of TNFR2 + Treg and related cytokines in patients with CIN and cervical cancer. Oncotarget. https://doi.org/10.18632/oncotarget.23581
Zhao X, Li Y, Wang X, Wu J, Yuan Y, Lv S, Ren J (2019) Synergistic association of FOXP3+ tumor infiltrating lymphocytes with CCL20 expressions with poor prognosis of primary breast cancer: a retrospective cohort study. Medicine 98(50):e18403–e18403. https://doi.org/10.1097/MD.0000000000018403
Zuo T, Liu R, Zhang H, Chang X, Liu Y, Wang L, Zheng P, Liu Y (2007) FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Investig 117(12):3765–3773. https://doi.org/10.1172/JCI32538
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We thank Christina Kuhn, Andrea Sendelhofert and Anja Heier for their excellent technical assistance.
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This study was funded by the Friedrich-Baur Foundation, LMU Munich.
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by NK, AV, TK and LH. The first draft of the manuscript was written by NK, AV and TK and all authors commented on previous versions of the manuscript. All authors analysed and interpreted the data and read and approved the final manuscript.
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Sven Mahner: Research support, advisory board Honoria and travel expenses from AbbVie, Astra Zeneca, Clovis, Eisai, GSK, Medac, MSD, Novartis, Olympus, PharmaMar, Roche, Sensor Kinesis, Teva, Tesaro. Thomas Kolben: Holding stocks of Roche AG, relative working at Roche AG. Anna Hester: Honoraria and travel expenses from Pfizer, Honoraria from Roche, Research funding from “Walter-Schulz-Stiftung”.
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Vattai, A., Kremer, N., Meister, S. et al. Role of FoxP3-positive regulatory T-cells in regressive and progressive cervical dysplasia. J Cancer Res Clin Oncol 148, 377–386 (2022). https://doi.org/10.1007/s00432-021-03838-6
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DOI: https://doi.org/10.1007/s00432-021-03838-6