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Erschienen in: Cancer Immunology, Immunotherapy 7/2011

01.07.2011 | Original article

Identification of Hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) as a CD8+ T-cell-defined human tumor antigen of human carcinomas

verfasst von: Carmen Visus, Diasuke Ito, Rajiv Dhir, Miroslaw J. Szczepanski, Yoo Jung Chang, Jean J. Latimer, Stephen G. Grant, Albert B. DeLeo

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2011

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Abstract

Hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) is a multifunctional isoenzyme functional in the conversion of estrone to estradiol (E2), and elongation of long-chain fatty acids, in particular the conversion of palmitic to archadonic (AA) acid, the precursor of sterols and the inflammatory mediator, prostaglandin E2. Its overexpression together with that of COX-2 in breast carcinoma is associated with a poor prognosis. We have identified the HSD17B12114–122 peptide (IYDKIKTGL) as a naturally presented HLA-A*0201 (HLA-A2)-restricted CD8+ T-cell-defined epitope. The HSD17B12114–122 peptide, however, is poorly immunogenic in its in vitro ability to induce peptide-specific CD8+ T cells. Acting as an “optimized peptide”, a peptide (TYDKIKTGL), which is identical to the HSD17B12114–122 peptide except for threonine at residue 1, was required for inducing in vitro the expansion of CD8+ T-cell effectors cross-reactive against the HSD17B12114–122 peptide. In IFN-γ ELISPOT assays, these effector cells recognize HSD17B12114–122 peptide-pulsed target cells, as well as HLA-A2+ squamous cell carcinoma of the head and neck (SCCHN) and breast carcinoma cell lines overexpressing HSD17B12 and naturally presenting the epitope. Whereas growth inhibition of a breast carcinoma cell line induced by HSD17B12 knockdown was only reversed by AA, in a similar manner, the growth inhibition of the SCCHN PCI-13 cell line by HSD17B12 knockdown was reversed by E2 and AA. Our findings provide the basis for future studies aimed at developing cancer vaccines for targeting HSD17B12, which apparently can be functional in critical metabolic pathways involved in inflammation and cancer.
Literatur
1.
Zurück zum Zitat Moeller G, Adamski J (2009) Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 301:7–19PubMedCrossRef Moeller G, Adamski J (2009) Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 301:7–19PubMedCrossRef
2.
Zurück zum Zitat Nagasaki S, Miki Y, Akahira J, Suzuki T, Sasano H (2009) Transcriptional regulation of 17beta-hydroxysteroid dehydrogenase type 12 by SREBP-1. Mol Cell Endocrinol 307:163–168PubMedCrossRef Nagasaki S, Miki Y, Akahira J, Suzuki T, Sasano H (2009) Transcriptional regulation of 17beta-hydroxysteroid dehydrogenase type 12 by SREBP-1. Mol Cell Endocrinol 307:163–168PubMedCrossRef
3.
Zurück zum Zitat Luu-The V, Tremblay P, Labrie F (2006) Characterization of type 12 17ß-hydroxysteroid dehydrogenase, an isoform of type 3 17ß-hydroxysteroid dehydrogenase responsible for estradiol formation in women. Mol Endocrinol 20:437–443PubMedCrossRef Luu-The V, Tremblay P, Labrie F (2006) Characterization of type 12 17ß-hydroxysteroid dehydrogenase, an isoform of type 3 17ß-hydroxysteroid dehydrogenase responsible for estradiol formation in women. Mol Endocrinol 20:437–443PubMedCrossRef
4.
Zurück zum Zitat Moon YA, Horton JD (2003) Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade. J Biol Chem 278:7335–7343PubMedCrossRef Moon YA, Horton JD (2003) Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade. J Biol Chem 278:7335–7343PubMedCrossRef
5.
Zurück zum Zitat Harizi H, Corcuff JB, Gualde N (2008) Arachidonic-acid derived eicosanoids: roles in biology and immunopathology. Trends Mol Med 14:461–469PubMedCrossRef Harizi H, Corcuff JB, Gualde N (2008) Arachidonic-acid derived eicosanoids: roles in biology and immunopathology. Trends Mol Med 14:461–469PubMedCrossRef
6.
Zurück zum Zitat Sakurai N, Miki Y, Suzuki T, Watanabe K, Narita T, Ando K, Yung TM, Aoki D, Sasano H, Handa H (2006) Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12. J Steroid Biochem Mol Biol 99:174–181PubMedCrossRef Sakurai N, Miki Y, Suzuki T, Watanabe K, Narita T, Ando K, Yung TM, Aoki D, Sasano H, Handa H (2006) Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12. J Steroid Biochem Mol Biol 99:174–181PubMedCrossRef
7.
Zurück zum Zitat Bellemare V, Laberge P, Noël S, Tchernof A, Luu-The V (2009) Differential estrogenic 17beta-hydroxysteroid dehydrogenase activity and type 12 17beta-hydroxysteroid dehydrogenase expression levels in preadipocytes and differentiated adipocytes. J Steroid Biochem Mol Biol 114:129–134PubMedCrossRef Bellemare V, Laberge P, Noël S, Tchernof A, Luu-The V (2009) Differential estrogenic 17beta-hydroxysteroid dehydrogenase activity and type 12 17beta-hydroxysteroid dehydrogenase expression levels in preadipocytes and differentiated adipocytes. J Steroid Biochem Mol Biol 114:129–134PubMedCrossRef
8.
Zurück zum Zitat Rantakari P, Lagerbohm H, Kaimainen M, Suomela JP, Strauss L, Sainio K, Pakarinen P, Poutanen M (2010) Hydroxysteroid (17{beta}) dehydrogenase 12 is essential for mouse organogenesis and embryonic survival. Endocrinology 151:1893–1901PubMedCrossRef Rantakari P, Lagerbohm H, Kaimainen M, Suomela JP, Strauss L, Sainio K, Pakarinen P, Poutanen M (2010) Hydroxysteroid (17{beta}) dehydrogenase 12 is essential for mouse organogenesis and embryonic survival. Endocrinology 151:1893–1901PubMedCrossRef
9.
Zurück zum Zitat Bellemare V, Phaneuf D, Luu-The V (2010) Target deletion of the bifunctional type 12 17b-hydroxysteroid dehydrogenase in mice results in reduction of androgen and estrogen levels in heterozygotes and embryonic lethality in homozygotes. Horm Biol Clin Investig 2:311–318CrossRef Bellemare V, Phaneuf D, Luu-The V (2010) Target deletion of the bifunctional type 12 17b-hydroxysteroid dehydrogenase in mice results in reduction of androgen and estrogen levels in heterozygotes and embryonic lethality in homozygotes. Horm Biol Clin Investig 2:311–318CrossRef
10.
Zurück zum Zitat Ito K, Utsunomiya H, Suzuki T, Saitou S, Akahira J, Okamura K, Yaegashi N, Sasano H (2006) 17Beta-hydroxysteroid dehydrogenases in human endometrium and its disorders. Mol Cell Endocrinol 248:136–140PubMedCrossRef Ito K, Utsunomiya H, Suzuki T, Saitou S, Akahira J, Okamura K, Yaegashi N, Sasano H (2006) 17Beta-hydroxysteroid dehydrogenases in human endometrium and its disorders. Mol Cell Endocrinol 248:136–140PubMedCrossRef
11.
Zurück zum Zitat Song D, Liu G, Luu-The V, Zhao D, Wang L, Zhang H, Xueling G, Li S, Désy L, Labrie F, Pelletier G (2006) Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study. J Steroid Biochem Mol Biol 101:136–144PubMedCrossRef Song D, Liu G, Luu-The V, Zhao D, Wang L, Zhang H, Xueling G, Li S, Désy L, Labrie F, Pelletier G (2006) Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study. J Steroid Biochem Mol Biol 101:136–144PubMedCrossRef
12.
Zurück zum Zitat Fournier MA, Poirier D (2009) Estrogen formation in endometrial and cervix cancer cell lines: involvement of aromatase, steroid sulfatase and 17beta-hydroxysteroid dehydrogenases (types 1, 5, 7 and 12). Mol Cell Endocrinol 301:142–145PubMedCrossRef Fournier MA, Poirier D (2009) Estrogen formation in endometrial and cervix cancer cell lines: involvement of aromatase, steroid sulfatase and 17beta-hydroxysteroid dehydrogenases (types 1, 5, 7 and 12). Mol Cell Endocrinol 301:142–145PubMedCrossRef
13.
Zurück zum Zitat Day JM, Foster PA, Tutill HJ, Parsons MF, Newman SP, Chander SK, Allan GM, Lawrence HR, Vicker N, Potter BV, Reed MJ, Purohit A (2008) 17beta-hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-dependent breast cancer. Int J Cancer 122:1931–1940PubMedCrossRef Day JM, Foster PA, Tutill HJ, Parsons MF, Newman SP, Chander SK, Allan GM, Lawrence HR, Vicker N, Potter BV, Reed MJ, Purohit A (2008) 17beta-hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-dependent breast cancer. Int J Cancer 122:1931–1940PubMedCrossRef
14.
Zurück zum Zitat Nagasaki S, Suzuki T, Miki Y, Akahira J, Kitada K, Ishida T, Handa H, Ohuchi N, Sasano H (2009) 17Beta-hydroxysteroid dehydrogenase type 12 in human breast carcinoma: a prognostic factor via potential regulation of fatty acid synthesis. Cancer Res 69:1392–1399PubMedCrossRef Nagasaki S, Suzuki T, Miki Y, Akahira J, Kitada K, Ishida T, Handa H, Ohuchi N, Sasano H (2009) 17Beta-hydroxysteroid dehydrogenase type 12 in human breast carcinoma: a prognostic factor via potential regulation of fatty acid synthesis. Cancer Res 69:1392–1399PubMedCrossRef
15.
Zurück zum Zitat Rickman DS, Millon R, De Reynies A, Thomas E, Wasylyk C, Muller D, Abecassis J, Wasylyk B (2008) Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene 27:6607–6622PubMedCrossRef Rickman DS, Millon R, De Reynies A, Thomas E, Wasylyk C, Muller D, Abecassis J, Wasylyk B (2008) Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene 27:6607–6622PubMedCrossRef
16.
Zurück zum Zitat Hendrickson RC, Cicinnati VR, Albers A, Dworacki G, Gambotto A, Pagliano O, Tüting T, Mayordomo JI, Visus C, Appella E, Shabanowitz J, Hunt DF, DeLeo AB (2010) Identification of a 17beta-hydroxysteroid dehydrogenase type 12 pseudogene as the source of a highly restricted BALB/c Meth A tumor rejection peptide. Cancer Immunol Immunother 59:113–124PubMedCrossRef Hendrickson RC, Cicinnati VR, Albers A, Dworacki G, Gambotto A, Pagliano O, Tüting T, Mayordomo JI, Visus C, Appella E, Shabanowitz J, Hunt DF, DeLeo AB (2010) Identification of a 17beta-hydroxysteroid dehydrogenase type 12 pseudogene as the source of a highly restricted BALB/c Meth A tumor rejection peptide. Cancer Immunol Immunother 59:113–124PubMedCrossRef
17.
Zurück zum Zitat Heo DS, Snyderman C, Gollin SM, Pan S, Walker E, Deka R, Barnes EL, Johnson JT, Herberman RB, Whiteside TL (1989) Biology, cytogenetics, and sensitivity to immunological effector cells of new head and neck squamous cell carcinoma lines. Cancer Res 49:5167–5175PubMed Heo DS, Snyderman C, Gollin SM, Pan S, Walker E, Deka R, Barnes EL, Johnson JT, Herberman RB, Whiteside TL (1989) Biology, cytogenetics, and sensitivity to immunological effector cells of new head and neck squamous cell carcinoma lines. Cancer Res 49:5167–5175PubMed
18.
Zurück zum Zitat Latimer JJ (2000) U.S. patent #6074874. Epithelial cell cultures useful for in vitro testing Latimer JJ (2000) U.S. patent #6074874. Epithelial cell cultures useful for in vitro testing
19.
Zurück zum Zitat Tsujisaki M, Sakaguchi K, Igarashi M, Richiardi P, Perosa F, Ferrone S (1988) Fine specificity and idiotype diversity of the murine anti-HLA-A2, A28 monoclonal antibodies CR11–351 and KS1. Transplantation 45:632–639PubMedCrossRef Tsujisaki M, Sakaguchi K, Igarashi M, Richiardi P, Perosa F, Ferrone S (1988) Fine specificity and idiotype diversity of the murine anti-HLA-A2, A28 monoclonal antibodies CR11–351 and KS1. Transplantation 45:632–639PubMedCrossRef
20.
Zurück zum Zitat Visus C, Ito D, Amoscato A, Maciejewska-Franczak M, Abdelsalem A, Dhir R, Shin DM, Donnenberg VS, Whiteside TL, DeLeo AB (2007) Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck. Cancer Res 67:10538–10545PubMedCrossRef Visus C, Ito D, Amoscato A, Maciejewska-Franczak M, Abdelsalem A, Dhir R, Shin DM, Donnenberg VS, Whiteside TL, DeLeo AB (2007) Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck. Cancer Res 67:10538–10545PubMedCrossRef
21.
Zurück zum Zitat Bergmannn CC, Yao Q, Ho CK, Buckwold L (1996) Flanking residues alter antigenicity and immunogenicity of multi-unit CTL epitopes. J Immunol 157:3242–3249 Bergmannn CC, Yao Q, Ho CK, Buckwold L (1996) Flanking residues alter antigenicity and immunogenicity of multi-unit CTL epitopes. J Immunol 157:3242–3249
22.
Zurück zum Zitat Gileadi U, Gallimore A, Van der Bruggen P, Cerundolo V (1999) Effect of epitope flanking residues on the presentation of N-terminal cytotoxic T lymphocyte epitopes. Eur J Immunol 29:2213–2222PubMedCrossRef Gileadi U, Gallimore A, Van der Bruggen P, Cerundolo V (1999) Effect of epitope flanking residues on the presentation of N-terminal cytotoxic T lymphocyte epitopes. Eur J Immunol 29:2213–2222PubMedCrossRef
23.
Zurück zum Zitat Hoffmann TK, Loftus DJ, Nakano K, Maeurer MJ, Chikamatsu K, Appella E, Whiteside TL, DeLeo AB (2002) The ability of variant peptides to reverse the nonresponsiveness of T lymphocytes to the wild-type sequence p53(264–272) epitope. J Immunol 168:1338–1347PubMed Hoffmann TK, Loftus DJ, Nakano K, Maeurer MJ, Chikamatsu K, Appella E, Whiteside TL, DeLeo AB (2002) The ability of variant peptides to reverse the nonresponsiveness of T lymphocytes to the wild-type sequence p53(264–272) epitope. J Immunol 168:1338–1347PubMed
24.
Zurück zum Zitat López-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, Ferrone S, Ferris RL (2006) Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 176:3402–3409PubMed López-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, Ferrone S, Ferris RL (2006) Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 176:3402–3409PubMed
25.
Zurück zum Zitat Gamzatova Z, Villabona L, Dahlgren L, Dalianis T, Nillson B, Bergfeldt K, Masucci GV (2006) Human leucocyte antigen (HLA) A2 as a negative clinical prognostic factor in patients with advanced ovarian cancer. Gynecol Oncol 103:145–150PubMedCrossRef Gamzatova Z, Villabona L, Dahlgren L, Dalianis T, Nillson B, Bergfeldt K, Masucci GV (2006) Human leucocyte antigen (HLA) A2 as a negative clinical prognostic factor in patients with advanced ovarian cancer. Gynecol Oncol 103:145–150PubMedCrossRef
26.
Zurück zum Zitat Seliger B, Kanter L, Dalianis T, Bergfeldt K, Masucci GV (2007) Analysis of HLA class I-II haplotype frequency and segregation in a cohort of patients with advanced stage ovarian cancer. Tissue Antigens 70:205–213PubMedCrossRef Seliger B, Kanter L, Dalianis T, Bergfeldt K, Masucci GV (2007) Analysis of HLA class I-II haplotype frequency and segregation in a cohort of patients with advanced stage ovarian cancer. Tissue Antigens 70:205–213PubMedCrossRef
27.
Zurück zum Zitat Norell H, Carlsten M, Ohlum T, Malmberg KJ, Masucci G, Schedvins K, Altermann W, Handke D, Atkins D, Seliger B, Kiessling R (2006) Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387–6394PubMedCrossRef Norell H, Carlsten M, Ohlum T, Malmberg KJ, Masucci G, Schedvins K, Altermann W, Handke D, Atkins D, Seliger B, Kiessling R (2006) Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387–6394PubMedCrossRef
28.
Zurück zum Zitat Egloff AM, Rothstein ME, Seethala R, Siegfried JM, Grandis JR, Stabile LP (2009) Cross-talk between estrogen receptor and epidermal growth factor receptor in head and neck squamous cell carcinoma. Clin Cancer Res 15:6529–6540PubMedCrossRef Egloff AM, Rothstein ME, Seethala R, Siegfried JM, Grandis JR, Stabile LP (2009) Cross-talk between estrogen receptor and epidermal growth factor receptor in head and neck squamous cell carcinoma. Clin Cancer Res 15:6529–6540PubMedCrossRef
29.
Zurück zum Zitat Snyderman CH, Klapan I, Milanovich M, Heo DS, Wagner R, Schwartz D, Johnson JT, Whiteside TL (1994) Comparison of in vivo and in vitro prostaglandin E2 production by squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 111:189–196PubMedCrossRef Snyderman CH, Klapan I, Milanovich M, Heo DS, Wagner R, Schwartz D, Johnson JT, Whiteside TL (1994) Comparison of in vivo and in vitro prostaglandin E2 production by squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 111:189–196PubMedCrossRef
30.
Zurück zum Zitat Snyderman CH, Klapan I, Milanovich M, Heo DS, Wagner R, Schwartz D, Johnson JT, Whiteside TL (2001) Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 3:53–61CrossRef Snyderman CH, Klapan I, Milanovich M, Heo DS, Wagner R, Schwartz D, Johnson JT, Whiteside TL (2001) Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 3:53–61CrossRef
31.
Zurück zum Zitat Kuhajda FP (2006) Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 66:5977–5980PubMedCrossRef Kuhajda FP (2006) Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 66:5977–5980PubMedCrossRef
Metadaten
Titel
Identification of Hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) as a CD8+ T-cell-defined human tumor antigen of human carcinomas
verfasst von
Carmen Visus
Diasuke Ito
Rajiv Dhir
Miroslaw J. Szczepanski
Yoo Jung Chang
Jean J. Latimer
Stephen G. Grant
Albert B. DeLeo
Publikationsdatum
01.07.2011
Verlag
Springer-Verlag
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 7/2011
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-1001-y

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