Role of FoxP3-positive regulatory T-cells in regressive and progressive cervical dysplasia.
Adolescent
Adult
Biomarkers, Tumor
/ metabolism
Disease Progression
Female
Forkhead Transcription Factors
/ metabolism
Germany
Humans
Immunohistochemistry
Middle Aged
Neoplasm Regression, Spontaneous
/ pathology
Papillomavirus Infections
/ immunology
Prognosis
T-Lymphocytes, Regulatory
/ metabolism
Uterine Cervical Neoplasms
/ diagnosis
Young Adult
Uterine Cervical Dysplasia
/ diagnosis
Cervical intraepithelial neoplasia
Conisation
FoxP3
HPV
Regulatory T-cells
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
24
08
2021
accepted:
14
09
2021
pubmed:
6
11
2021
medline:
8
2
2022
entrez:
5
11
2021
Statut:
ppublish
Résumé
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). 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). 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). 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.
Identifiants
pubmed: 34739585
doi: 10.1007/s00432-021-03838-6
pii: 10.1007/s00432-021-03838-6
doi:
Substances chimiques
Biomarkers, Tumor
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
377-386Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
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
doi: 10.1111/j.1600-0897.2008.00590.x
pubmed: 18593438
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
doi: 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
doi: 10.1136/jcp.51.2.96
pubmed: 9602680
pmcid: 500501
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
doi: 10.1016/j.jid.2019.03.1162
pubmed: 31207230
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
doi: 10.1002/jmv.25312
pubmed: 30192406
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
doi: 10.1073/pnas.89.10.4549
pubmed: 1316611
pmcid: 49120
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
doi: 10.1200/jco.18.01265
pubmed: 30943124
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
doi: 10.3389/fimmu.2019.03136
pubmed: 32117202
pmcid: 7008726
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
doi: 10.1016/j.coi.2008.04.008
pubmed: 18508251
pmcid: 3319305
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
doi: 10.1038/nm1093
pubmed: 15322536
pmcid: 15322536
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
doi: 10.1097/LGT.0b013e31825c31dd
pubmed: 22820980
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
doi: 10.1016/j.ygyno.2009.03.022
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
doi: 10.1007/s10585-013-9602-9
pubmed: 23836289
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
doi: 10.1158/1078-0432.Ccr-10-1073
pubmed: 20682706
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
doi: 10.1002/path.4381
pubmed: 24870556
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
doi: 10.1200/jco.2017.74.5471
pubmed: 29095678
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
doi: 10.1080/2162402X.2019.1593806
pubmed: 31143514
pmcid: 6527267
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
doi: 10.1016/j.virol.2003.08.008
pubmed: 14675634
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
doi: 10.1038/s41590-019-0555-2
pubmed: 31844326
Hinz S (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Can Res 67:8344–8350
doi: 10.1158/0008-5472.CAN-06-3304
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
doi: 10.1007/s00345-015-1615-3
pubmed: 26055646
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
doi: 10.3349/ymj.2008.49.6.942
pubmed: 19108017
pmcid: 2628022
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
doi: 10.3389/fimmu.2019.00911
pubmed: 31134056
pmcid: 6517506
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
doi: 10.1158/1078-0432.Ccr-18-2740
pubmed: 30770348
pmcid: 7980952
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
doi: 10.1007/s00262-015-1753-x
pubmed: 26298430
pmcid: 4651184
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
doi: 10.1111/aji.12030
pubmed: 23057776
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
doi: 10.2217/fon-2016-0259
pubmed: 27646625
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
doi: 10.3802/jgo.2019.30.e42
pubmed: 30887760
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
doi: 10.1073/pnas.0811556106
pubmed: 19174509
pmcid: 2644136
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
doi: 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
doi: 10.1056/NEJMoa1917338
pubmed: 32997908
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
doi: 10.1038/s41419-018-0790-8
pubmed: 29970908
pmcid: 6030162
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
doi: 10.1111/j.1349-7006.2009.01153.x
pubmed: 19514119
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
doi: 10.1016/j.molmed.2007.01.003
pubmed: 17257897
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
doi: 10.1200/jco.19.00739
pubmed: 31487218
pmcid: 6823884
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
doi: 10.1111/cas.14069
pubmed: 31102428
pmcid: 6609813
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
doi: 10.1016/0090-8258(92)90483-Y
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
pubmed: 31497220
pmcid: 6731430
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
doi: 10.1016/j.ejca.2008.05.017
pubmed: 18617393
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
doi: 10.1111/j.1600-065X.2011.01018.x
pubmed: 21488902
pmcid: 3077798
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
doi: 10.1073/pnas.0509182102
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
doi: 10.1016/0092-8674(90)90409-8
pubmed: 2175676
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
doi: 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
doi: 10.1084/jem.20041982
pubmed: 15753206
pmcid: 2212841
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
doi: 10.1186/s12885-017-3633-6
pubmed: 28903735
pmcid: 5598072
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
doi: 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
doi: 10.1136/bmj.k499
pubmed: 29487049
pmcid: 5826010
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
doi: 10.1186/s12957-017-1221-5
pubmed: 28923073
pmcid: 5604510
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
doi: 10.1080/2162402x.2015.1064581
pubmed: 27057430
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
doi: 10.1111/j.1365-2249.2007.03468.x
pubmed: 17937675
pmcid: 2219359
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
doi: 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
doi: 10.1007/s00018-009-0026-2
pubmed: 19390784
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
doi: 10.1158/0008-5472.CAN-18-2049
pubmed: 30733194
pmcid: 6445690
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
doi: 10.1038/s41419-020-03272-5
pubmed: 33414414
pmcid: 7790820
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
doi: 10.1002/ijc.32782
pubmed: 31709528
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
doi: 10.1111/imm.13067
pubmed: 31087644
pmcid: 6587321
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
doi: 10.1084/jem.20041684
pubmed: 15753211
pmcid: 2212829
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
doi: 10.1007/s00262-012-1348-8
pubmed: 22986453
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
doi: 10.18632/oncotarget.23581
pubmed: 30546827
pmcid: 5814161
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
doi: 10.1097/MD.0000000000018403
pubmed: 31852159
pmcid: 6922488
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
doi: 10.1172/JCI32538
pubmed: 18008005
pmcid: 2075479