ERAP1 overexpression in HPV-induced malignancies: a possible novel immune evasion mechanism
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...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
28 Jun 2017
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| In: |
OncoImmunology
Year: 2017, Volume: 6, Issue: 7 |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402X.2017.1336594 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1080/2162402X.2017.1336594 Verlag, kostenfrei, Volltext: https://doi.org/10.1080/2162402X.2017.1336594 
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| Author Notes: | 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 |
| Summary: | 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. |
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| Item Description: | Gesehen am 17.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402X.2017.1336594 |