ERAP1 overexpression in HPV-induced malignancies

• Verfasst von: Steinbach, Alina [VerfasserIn]
• Verfasst von: Winter, Jan [VerfasserIn]
• Verfasst von: Reuschenbach, Miriam [VerfasserIn]
• Verfasst von: Blatnik, Renata [VerfasserIn]
• Verfasst von: Hoppe, Stephanie [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Verfasst von: Riemer, Angelika [VerfasserIn]
• Titel: ERAP1 overexpression in HPV-induced malignancies
• Titelzusatz: a possible novel immune evasion mechanism
• Verf.angabe: Alina Steinbach, Jan Winter, Miriam Reuschenbach, Renata Blatnik, Alexandra Klevenz, Miriam Bertrand, Stephanie Hoppe, Magnus von Knebel Doeberitz, Agnieszka K. Grabowska, and Angelika B. Riemer
• E-Jahr: 2017
• Jahr: 28 Jun 2017
• Umfang: 9 S.
• Teil: volume:6
• Teil: year:2017
• Teil: number:7
• Teil: extent:9
• Fussnoten: Gesehen am 17.09.2018
• Titel Quelle: Enthalten in: OncoImmunology
• Ort Quelle: Abingdon : Taylor & Franics, 2012
• Jahr Quelle: 2017
• Band/Heft Quelle: 6(2017,7) Artikel-Nummer e1336594, 9 Seiten
• ISSN Quelle: 2162-402X
• DOI: doi:10.1080/2162402X.2017.1336594
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antigen processing machinery (APM)
• Sach-SW: cervical cancer
• Sach-SW: endoplasmic reticulum aminopeptidase 1 (ERAP1)
• Sach-SW: human papillomavirus (HPV)
• Sach-SW: T-cell epitopes
• K10plus-PPN: 1581025947

Abstract

Immune evasion of tumors poses a major challenge for immunotherapy. For human papillomavirus (HPV)-induced malignancies, multiple immune evasion mechanisms have been described, including altered expression of antigen processing machinery (APM) components. These changes can directly influence epitope presentation and thus T-cell responses against tumor cells. To date, the APM had not been studied systematically in a large array of HPV+ tumor samples. Therefore in this study, systematic expression analysis of the APM was performed on the mRNA and protein level in a comprehensive collection of HPV16+ cell lines. Subsequently, HPV+ cervical tissue samples were examined by immunohistochemistry. ERAP1 (endoplasmic reticulum aminopeptidase 1) was the only APM component consistently altered - namely overexpressed - in HPV16+ tumor cell lines. ERAP1 was also found to be overexpressed in cervical intraepithelial neoplasia and cervical cancer samples; expression levels were increasing with disease stage. On the functional level, the influence of ERAP1 expression levels on HPV16 E7-derived epitope presentation was investigated by mass spectrometry and in cytotoxicity assays with HPV16-specific T-cell lines. ERAP1 overexpression did not cause a complete destruction of any of the HPV epitopes analyzed, however, an influence of ERAP1 overexpression on the presentation levels of certain HPV epitopes could be demonstrated by HPV16-specific CD8+ T-cells. These showed enhanced killing toward HPV16+ CaSki cells whose ERAP1 expression had been attenuated to normal levels. ERAP1 overexpression may thus represent a novel immune evasion mechanism in HPV-induced malignancies, in cases when presentation of clinically relevant epitopes is reduced by overactivity of this peptidase.