Indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase expression in HPV infection, SILs, and cervical cancer.
Biomarkers, Tumor
/ immunology
Carcinogenesis
/ immunology
Carcinoma, Squamous Cell
/ immunology
Cervix Uteri
/ immunology
Female
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ immunology
Middle Aged
Oligopeptides
Papanicolaou Test
Papillomaviridae
/ immunology
Papillomavirus Infections
/ immunology
Tryptophan Oxygenase
/ immunology
Up-Regulation
Uterine Cervical Neoplasms
/ immunology
Vaginal Smears
Uterine Cervical Dysplasia
/ immunology
cervical cancer
cervical intraepithelial neoplasia
human papillomavirus 16
indolamine-2,3-dioxygenase
squamous intraepithelial lesions
tryptophan 2,3-dioxygenase
Journal
Cancer cytopathology
ISSN: 1934-6638
Titre abrégé: Cancer Cytopathol
Pays: United States
ID NLM: 101499453
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
24
03
2019
revised:
21
07
2019
accepted:
22
07
2019
pubmed:
15
8
2019
medline:
28
5
2020
entrez:
15
8
2019
Statut:
ppublish
Résumé
Human papillomavirus (HPV) infection is the central factor for cervical cancer, whereas epithelial immune mechanisms contribute to the progression of HPV infection and its associated lesions. The authors evaluated the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) in cervicovaginal samples from women with normal cervical epithelium or with different degrees of squamous intraepithelial lesions (SILs) and cervical cancer. IDO expression was analyzed by immunocytochemistry in liquid-based cytology samples from 165 women, of whom 42 had cervical changes subclassified as low-grade SIL (n = 6), high-grade SIL (n = 30), or squamous cell carcinoma (SCC) (n = 6), and 123 had negative Papanicolaou smears. IDO and TDO expression also were analyzed by immunohistochemistry, and HPV and other genital pathogens were evaluated by polymerase chain reaction analysis. Low IDO expression was observed in normal cervical epithelium irrespective of HPV status. Increased numbers of IDO-positive squamous cells and IDO-positive leukocytes were observed in women with SIL or SCC. TDO expression was detected in leukocytes infiltrating the stroma around intraepithelial or invasive cervical lesions. Higher IDO levels were detected in organotypic epithelial cultures established from keratinocytes transduced with the HPV16 E6/E7 oncoproteins. The upregulation of IDO expression in leukocytes and squamous cells in HPV-associated SIL and SCC suggests that immunosuppressive mechanisms involving tryptophan metabolism may have a role in cervical carcinogenesis. Although previous studies have suggested the role of IDO in HPV pathogenesis, this is the first evidence of TDO involvement in the process. Furthermore, the current data emphasize the role of leukocytes, especially neutrophil-like cells, as an IDO source.
Sections du résumé
BACKGROUND
Human papillomavirus (HPV) infection is the central factor for cervical cancer, whereas epithelial immune mechanisms contribute to the progression of HPV infection and its associated lesions. The authors evaluated the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) in cervicovaginal samples from women with normal cervical epithelium or with different degrees of squamous intraepithelial lesions (SILs) and cervical cancer.
METHODS
IDO expression was analyzed by immunocytochemistry in liquid-based cytology samples from 165 women, of whom 42 had cervical changes subclassified as low-grade SIL (n = 6), high-grade SIL (n = 30), or squamous cell carcinoma (SCC) (n = 6), and 123 had negative Papanicolaou smears. IDO and TDO expression also were analyzed by immunohistochemistry, and HPV and other genital pathogens were evaluated by polymerase chain reaction analysis.
RESULTS
Low IDO expression was observed in normal cervical epithelium irrespective of HPV status. Increased numbers of IDO-positive squamous cells and IDO-positive leukocytes were observed in women with SIL or SCC. TDO expression was detected in leukocytes infiltrating the stroma around intraepithelial or invasive cervical lesions. Higher IDO levels were detected in organotypic epithelial cultures established from keratinocytes transduced with the HPV16 E6/E7 oncoproteins.
CONCLUSIONS
The upregulation of IDO expression in leukocytes and squamous cells in HPV-associated SIL and SCC suggests that immunosuppressive mechanisms involving tryptophan metabolism may have a role in cervical carcinogenesis. Although previous studies have suggested the role of IDO in HPV pathogenesis, this is the first evidence of TDO involvement in the process. Furthermore, the current data emphasize the role of leukocytes, especially neutrophil-like cells, as an IDO source.
Substances chimiques
Biomarkers, Tumor
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Oligopeptides
0
crosstide peptide
0
Tryptophan Oxygenase
EC 1.13.11.11
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
586-597Subventions
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : CNPQ 134385/2016-0
Pays : International
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2012/09746-2
Pays : International
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2017/04926-6
Pays : International
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : Procad 88881.068413/2014-01
Pays : International
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : 88881.068413/2014-01
Pays : International
Informations de copyright
© 2019 American Cancer Society.
Références
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
Franco E, Villa L, Rohan T, Ferenczy A, Petzl-Erler M, Matlashewski G. Design and methods of the Ludwig-McGill longitudinal study of the natural history of human papillomavirus infection and cervical neoplasia in Brazil. Ludwig-McGill Study Group. Rev Panam Salud Publica. 1999;6:223-233.
Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32(suppl):S7-S15.
Bravo IG, Felez-Sanchez M. Papillomaviruses: viral evolution, cancer and evolutionary medicine. Evol Med Public Health. 2015;2015:32-51.
Orlando PA, Gatenby RA, Giuliano AR, et al. Evolutionary ecology of human papillomavirus: trade-offs, coexistence, and origins of high-risk and low-risk types. J Infect Dis. 2012;205:272-279.
Steinbach A, Riemer AB. Immune evasion mechanisms of human papillomavirus: an update. Int J Cancer. 2018;142:224-229.
Alvarez KLF, Beldi M, Sarmanho F, et al. Local and systemic immunomodulatory mechanisms triggered by human papillomavirus transformed cells: a potential role for G-CSF and neutrophils. Sci Rep. 2017;7:9002.
Bashaw AA, Leggatt GR, Chandra J, Tuong ZK, Frazer IH. Modulation of antigen presenting cell functions during chronic HPV infection. Papillomavirus Res. 2017;4:58-65.
Patel S, Chiplunkar S. Host immune responses to cervical cancer. Curr Opin Obstet Gynecol. 2009;21:54-59.
Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2012;34:137-143.
Schmidt SV, Schultze JL. New insights into IDO biology in bacterial and viral infections. Front Immunol. 2014;5:384.
Bilir C, Sarisozen C. Indoleamine 2,3-dioxygenase (IDO): only an enzyme or a checkpoint controller? J Oncol Sci. 2017;3:52-56.
Platten M, von Knebel DN, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2014;5:673.
Mittal D, Kassianos AJ, Tran LS, et al. Indoleamine 2,3-dioxygenase activity contributes to local immune suppression in the skin expressing human papillomavirus oncoprotein E7. J Invest Dermatol. 2013;133:2686-2694.
Hascitha J, Priya R, Jayavelu S, et al. Analysis of kynurenine/tryptophan ratio and expression of IDO1 and 2 mRNA in tumour tissue of cervical cancer patients. Clin Biochem. 2016;49:919-924.
Kobayashi A, Weinberg V, Darragh T, Smith-McCune K. Evolving immunosuppressive microenvironment during human cervical carcinogenesis. Mucosal Immunol. 2008;1:412-420.
Ferns DM, Kema IP, Buist MR, Nijman HW, Kenter GG, Jordanova ES. Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival. Oncoimmunology. 2015;4:e981457.
Inaba T, Ino K, Kajiyama H, et al. Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy. Gynecol Oncol. 2010;117:423-428.
Yu CP, Fu SF, Chen X, et al. The clinicopathological and prognostic significance of IDO1 expression in human solid tumors: evidence from a systematic review and meta-analysis. Cell Physiol Biochem. 2018;49:134-143.
Selvan SR, Dowling JP, Kelly WK, Lin J. Indoleamine 2,3-dioxygenase (IDO): biology and target in cancer immunotherapies. Curr Cancer Drug Targets. 2016;16:755-764.
Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017;76:167-182.
Prendergast GC, Malachowski WP, Duhadaway JB, et al. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 2017;77:6795-6811.
Chen IC, Lee KH, Hsu YH, Wang WR, Chen CM, Cheng YW. Expression pattern and clinicopathological relevance of the indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase protein in colorectal cancer. Dis Markers. 2016;2016:8169724.
Zhai L, Spranger S, Binder DC, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res. 2015;21:5427-5433.
Bosnyak E, Kamson DO, Behen ME, Barger GR, Mittal S, Juhasz C. Imaging cerebral tryptophan metabolism in brain tumor-associated depression. EJNMMI Res. 2015;5:56.
Pilotte L, Larrieu P, Stroobant V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci USA. 2012;109:2497-2502.
Discacciati MG, Gimenes F, Pennacchi PC, et al. MMP-9/RECK imbalance: a mechanism associated with high-grade cervical lesions and genital infection by human papillomavirus and Chlamydia trachomatis. Cancer Epidemiol Biomarkers Prev. 2015;24:1539-1547.
Nayar R, Wilbur DC. The Pap test and Bethesda 2014. J Low Genit Tract Dis. 2015;19:175-184.
Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Volume 6. 4th ed. International Agency for Research on Cancer (IARC); 2014.
Souza RP, de Abreu AL, Ferreira EC, et al. Simultaneous detection of seven sexually transmitted agents in human immunodeficiency virus-infected Brazilian women by multiplex polymerase chain reaction. Am J Trop Med Hyg. 2013;30:1199-1202.
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:297-301.
Termini L, Boccardo E, Esteves GH, et al. Characterization of global transcription profile of normal and HPV immortalized keratinocytes and their response to TNF treatment. BMC Med Genomics. 2008;1:29.
Theate I, van Baren N, Pilotte L, et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res. 2015;3:161-172.
Nino-Castro A, Abdullah Z, Popov A, et al. The IDO1-induced kynurenines play a major role in the antimicrobial effect of human myeloid cells against Listeria monocytogenes. Innate Immun. 2014;20:401-411.
Romani L, Zelante T, De Luca A, et al. Microbiota control of a tryptophan-AhR pathway in disease tolerance to fungi. Eur J Immunol. 2014;44:3192-3200.
Dai X, Zhu BT. Indoleamine 2,3-dioxygenase tissue distribution and cellular localization in mice: implications for its biological functions. J Histochem Cytochem. 2010;58:17-28.
Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193-207.
Perobelli SM, Galvani RG, Goncalves-Silva T, Xavier CR, Nobrega A, Bonomo A. Plasticity of neutrophils reveals modulatory capacity. Braz J Med Biol Res. 2015;48:665-675.
Kruger P, Saffarzadeh M, Weber AN, et al. Neutrophils: between host defense, immune modulation, and tissue injury. PLoS Pathog. 2015;11:e1004651.
Loughman JA, Hunstad DA. Induction of indoleamine 2,3-dioxygenase by uropathogenic bacteria attenuates innate responses to epithelial infection. J Infect Dis. 2012;205:1830-1839.
Yu J, Wang Y, Yan F, Li H, Ren X. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013;190:3783-3797.
Galdiero MR, Bonavita E, Barajon I, Garlanda C, Mantovani A, Jaillon S. Tumor associated macrophages and neutrophils in cancer. Immunobiology. 2013;218:1402-1410.
Badalamenti G, Fanale D, Incorvaia L, et al. Role of tumor-infiltrating lymphocytes in patients with solid tumors: can a drop dig a stone [published online February 1, 2018]? Cell Immunol. doi:10.1006/j.cellimm.2018.01.013
Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006;86:231-145.
Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18:349-355.
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2”TAN. Cancer Cell. 2009;16:183-194.
Chimal-Ramírez GK, Espinoza-Sanchez NA, Fuentes-Panana EM. Protumor activities of the immune response: insights in the mechanisms of immunological shift, oncotraining, and oncopromotion. J Oncol. 2013;2013:835956.
Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.
Moses K, Brandau S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol. 2016;28:187-196.
Kawano M, Mabuchi S, Matsumoto Y, et al. The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep. 2015;5:18217.
Wu L, Liu H, Guo H, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in cervical carcinoma patients. Oncol Lett. 2018;15:9507-9515.
Punt S, Fleuren GJ, Kritikou E, et al. Angels and demons: Th17 cells represent a beneficial response, while neutrophil IL-17 is associated with poor prognosis in squamous cervical cancer. Oncoimmunology. 2015;4:e984539.
Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269-1274.
Lob S, Konigsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58:153-157.
Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2,3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci. 2007;98:874-881.
Sedlmayr P, Blaschitz A, Wintersteiger R, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol Hum Reprod. 2002;8:385-391.
Hjortso MC, Larsen SK, Kongsted P, et al. Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer. Oncoimmunology. 2015;4:e968480.
Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478:197-203.