Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
14 05 2020
14 05 2020
Historique:
received:
06
11
2019
accepted:
04
02
2020
revised:
28
01
2020
entrez:
16
5
2020
pubmed:
16
5
2020
medline:
5
5
2021
Statut:
epublish
Résumé
Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.
Identifiants
pubmed: 32409671
doi: 10.1038/s41408-020-0324-3
pii: 10.1038/s41408-020-0324-3
pmc: PMC7225173
doi:
Substances chimiques
Enterotoxins
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
57Références
Berg, S., Villasenor-Park, J., Haun, P. & Kim, E. J. Multidisciplinary management of mycosis Fungoides/Sezary Syndrome. Curr. Hematol. Malig. Rep. 12, 234–243 (2017).
pubmed: 28540671
doi: 10.1007/s11899-017-0387-9
Kim, E. J. et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J. Clin. Investig. 115, 798–812 (2005).
pubmed: 15841167
doi: 10.1172/JCI24826
Girardi, M., Heald, P. W. & Wilson, L. D. The pathogenesis of mycosis fungoides. N. Engl. J. Med. 350, 1978–1988 (2004).
pubmed: 15128898
doi: 10.1056/NEJMra032810
Wang, L. et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat. Genet. 47, 1426–1434 (2015).
pubmed: 26551670
pmcid: 4829974
doi: 10.1038/ng.3444
Ungewickell, A. et al. Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nat. Genet. 47, 1056–1060 (2015).
pubmed: 26258847
pmcid: 6091217
doi: 10.1038/ng.3370
da Silva Almeida, A. C. et al. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nat. Genet. 47, 1465–1470 (2015).
pubmed: 26551667
pmcid: 4878831
doi: 10.1038/ng.3442
Choi, J. et al. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet. 47, 1011–1019 (2015).
pubmed: 26192916
pmcid: 4552614
doi: 10.1038/ng.3356
Scarisbrick, J. J., Woolford, A. J., Russell-Jones, R. & Whittaker, S. J. Loss of heterozygosity on 10q and microsatellite instability in advanced stages of primary cutaneous T-cell lymphoma and possible association with homozygous deletion of PTEN. Blood 95, 2937–2942 (2000).
pubmed: 10779442
doi: 10.1182/blood.V95.9.2937.009k15_2937_2942
Mao, X. et al. Molecular cytogenetic characterization of Sezary syndrome. Genes Chromosomes Cancer 36, 250–260 (2003).
pubmed: 12557225
doi: 10.1002/gcc.10152
Bastidas Torres, A. N. et al. Genomic analysis reveals recurrent deletion of JAK-STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides. Genes Chromosomes Cancer 57, 653–664 (2018).
pubmed: 30144205
pmcid: 6282857
doi: 10.1002/gcc.22679
Buus, T. B. et al. Single-cell heterogeneity in Sezary syndrome. Blood Adv. 2, 2115–2126 (2018).
pubmed: 30139925
pmcid: 6113609
doi: 10.1182/bloodadvances.2018022608
Guenova E., et al. TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin. Cancer Res. 19, 3755–3763 (2013).
Lee, B. N. et al. Dysregulated synthesis of intracellular type 1 and type 2 cytokines by T cells of patients with cutaneous T-cell lymphoma. Clin. Diagn. Lab. Immunol. 6, 79–84 (1999).
pubmed: 9874668
pmcid: 95664
doi: 10.1128/CDLI.6.1.79-84.1999
Vowels, B. R., Cassin, M., Vonderheid, E. C. & Rook, A. H. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J. Invest. Dermatol. 99, 90–94 (1992).
pubmed: 1607682
doi: 10.1111/1523-1747.ep12611877
Yamanaka, K. et al. Expression of interleukin-18 and caspase-1 in cutaneous T-cell lymphoma. Clin. Cancer Res. 12, 376–382 (2006).
pubmed: 16428475
doi: 10.1158/1078-0432.CCR-05-1777
Wysocka, M. et al. Sezary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines. Blood 100, 3287–3294 (2002).
pubmed: 12384429
doi: 10.1182/blood-2002-01-0231
Zhang, Q. et al. Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. Proc. Natl Acad. Sci. USA 93, 9148–9153 (1996).
pubmed: 8799169
doi: 10.1073/pnas.93.17.9148
Kasprzycka, M. et al. Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes. J. Immunol. 181, 2506–2512 (2008).
pubmed: 18684941
pmcid: 2586884
doi: 10.4049/jimmunol.181.4.2506
Krejsgaard, T. et al. Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome. Leukemia 22, 2230–2239 (2008).
pubmed: 18769452
doi: 10.1038/leu.2008.224
Krejsgaard, T. et al. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation. Blood 124, 761–770 (2014).
pubmed: 24957145
pmcid: 4118485
doi: 10.1182/blood-2014-01-551184
Bouaziz, J. D. et al. Circulating natural killer lymphocytes are potential cytotoxic effectors against autologous malignant cells in sezary syndrome patients. J. Invest. Dermatol. 125, 1273–1278 (2005).
pubmed: 16354199
doi: 10.1111/j.0022-202X.2005.23914.x
Wilcox, R. A. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 92, 1085–1102 (2017).
pubmed: 28872191
doi: 10.1002/ajh.24876
Berger, C. L. et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 105, 1640–1647 (2005).
pubmed: 15514008
doi: 10.1182/blood-2004-06-2181
Klemke, C. D. et al. Histopathological and immunophenotypical criteria for the diagnosis of Sezary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases. B. J. Dermatol. 173, 93–105 (2015).
doi: 10.1111/bjd.13832
Klemke, C. D. et al. Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sezary syndrome from other cutaneous T-cell lymphomas. Leukemia 20, 1123–1129 (2006).
pubmed: 16557241
doi: 10.1038/sj.leu.2404182
Capriotti, E. et al. Expression of T-plastin, FoxP3 and other tumor-associated markers by leukemic T-cells of cutaneous T-cell lymphoma. Leuk. Lymphoma 49, 1190–1201 (2008).
pubmed: 18569641
pmcid: 3983987
doi: 10.1080/10428190802064917
Heid, J. B. et al. FOXP3+CD25- tumor cells with regulatory function in Sezary syndrome. J. Invest. Dermatol. 129, 2875–2885 (2009).
pubmed: 19626037
doi: 10.1038/jid.2009.175
Shareef, M. M., Elgarhy, L. H. & Wasfy Rel, S. Expression of Granulysin and FOXP3 in Cutaneous T Cell Lymphoma and Sezary Syndrome. Asian Pac. J. Cancer Prev. 16, 5359–5364 (2015).
pubmed: 26225678
doi: 10.7314/APJCP.2015.16.13.5359
Wada, D. A., Wilcox, R. A., Weenig, R. H. & Gibson, L. E. Paucity of intraepidermal FoxP3-positive T cells in cutaneous T-cell lymphoma in contrast with spongiotic and lichenoid dermatitis. J. Cutan. Pathol. 37, 535–541 (2010).
pubmed: 19674197
doi: 10.1111/j.1600-0560.2009.01381.x
Borcherding, N. et al. Single-cell profiling of cutaneous T-cell lymphoma reveals underlying heterogeneity associated with disease progression. Clin Cancer Res. 25, 2996–3005 (2019).
pubmed: 30718356
doi: 10.1158/1078-0432.CCR-18-3309
pmcid: 6659117
Blaizot, R., Ouattara, E., Fauconneau, A., Beylot-Barry, M. & Pham-Ledard, A. Infectious events and associated risk factors in mycosis fungoides/Sezary syndrome: a retrospective cohort study. Br. J. Dermatol. 179, 1322–1328 (2018).
pubmed: 30098016
doi: 10.1111/bjd.17073
Axelrod, P. I., Lorber, B. & Vonderheid, E. C. Infections complicating mycosis fungoides and Sezary syndrome. JAMA 267, 1354–1358 (1992).
pubmed: 1740857
doi: 10.1001/jama.1992.03480100060031
Mirvish, E. D., Pomerantz, R. G. & Geskin, L. J. Infectious agents in cutaneous T-cell lymphoma. J. Am. Acad. Dermatol. 64, 423–431 (2011).
pubmed: 20692726
doi: 10.1016/j.jaad.2009.11.692
Odum, N. et al. Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins. Blood Cancer J. 7, e517 (2017).
pubmed: 28106877
pmcid: 5301035
doi: 10.1038/bcj.2016.128
Thode, C. et al. Malignant T cells secrete galectins and induce epidermal hyperproliferation and disorganized stratification in a skin model of cutaneous T-cell lymphoma. J. Invest. Dermatol. 135, 238–246 (2015).
pubmed: 25007045
doi: 10.1038/jid.2014.284
Posner, L. E., Fossieck, B. E. Jr, Eddy, J. L. & Bunn, P. A. Jr Septicemic complications of the cutaneous T-cell lymphomas. Am. J. Med. 71, 210–216 (1981).
pubmed: 6973273
doi: 10.1016/0002-9343(81)90107-8
Baser, S., Onn, A., Lin, E., Morice, R. C. & Duvic, M. Pulmonary manifestations in patients with cutaneous T-cell lymphomas. Cancer 109, 1550–1555 (2007).
pubmed: 17351938
doi: 10.1002/cncr.22567
Willerslev-Olsen A., et al. Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood 127, 1287–1296 (2016).
Willerslev-Olsen, A. et al. Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma. Toxins 5, 1402–1421 (2013).
pubmed: 23949004
pmcid: 3760043
doi: 10.3390/toxins5081402
Lindahl L. M., et al. Antibiotics inhibit tumor and disease activity in cutaneous T cell lymphoma. Blood 134, 1072–1083 (2019).
Willemze, R. et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 105, 3768–3785 (2005).
pubmed: 15692063
doi: 10.1182/blood-2004-09-3502
Kaltoft, K. et al. A continuous T-cell line from a patient with Sezary syndrome. Arch. Dermatol. Res. 279, 293–298 (1987).
pubmed: 3498444
doi: 10.1007/BF00431220
Krejsgaard T., et al. Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma. Blood 122, 943–950 (2013).
Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 108, 1571–1579 (2006).
pubmed: 16645171
pmcid: 1895505
doi: 10.1182/blood-2006-02-004747
Fujii, H. et al. Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission. Proc. Natl Acad. Sci. USA 92, 5482–5486 (1995).
pubmed: 7777534
doi: 10.1073/pnas.92.12.5482
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).
pubmed: 16227984
doi: 10.1038/ni1263
Ko, H. S., Fu, S. M., Winchester, R. J., Yu, D. T. & Kunkel, H. G. Ia determinants on stimulated human T lymphocytes. Occurrence on mitogen- and antigen-activated T cells. J. Exp. Med. 150, 246–255 (1979).
pubmed: 88499
doi: 10.1084/jem.150.2.246
Woetmann, A. et al. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins. Blood 109, 3325–3332 (2007).
pubmed: 17179233
pmcid: 1852254
doi: 10.1182/blood-2006-04-017863
Odum, N., Kanner, S. B., Ledbetter, J. A. & Svejgaard, A. MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors. J. Immunol. 150, 5289–5298 (1993).
pubmed: 8515060
Fraser, J. D. & Proft, T. The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 225, 226–243 (2008).
pubmed: 18837785
doi: 10.1111/j.1600-065X.2008.00681.x
Jackow, C. M. et al. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion. Blood. 89, 32–40 (1997).
pubmed: 8978274
doi: 10.1182/blood.V89.1.32
Hamrouni, A., Fogh, H., Zak, Z., Odum, N. & Gniadecki, R. Clonotypic Diversity of the T-cell Receptor Corroborates the Immature Precursor Origin of Cutaneous T-cell Lymphoma. Clin Cancer Res. 25, 3104–3114 (2019).
pubmed: 30808775
doi: 10.1158/1078-0432.CCR-18-4099
Gaydosik, A. M. et al. Single-cell lymphocyte heterogeneity in advanced cutaneous T-cell lymphoma skin tumors. Clin. Cancer Res. 25, 4443–4454 (2019).
pubmed: 31010835
doi: 10.1158/1078-0432.CCR-19-0148