ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism

OncoImmunology

Miriam Bertrand¹  Renata Blatnik¹  Stephanie Hoppe¹  Alexandra Klevenz¹  Angelika B. Riemer¹  Alina Steinbach¹  Jan Winter¹  Agnieszka K. Grabowska¹  Miriam Reuschenbach²  Magnus von Knebel Doeberitz² 

[1] Immunotherapy & Immunoprevention, German Cancer Research Center (DKFZ);Institute of Pathology, University of Heidelberg;

关键词: antigen processing machinery (apm);    cervical cancer;    endoplasmic reticulum aminopeptidase 1 (erap1);    human papillomavirus (hpv);    t-cell epitopes;   

DOI  :  10.1080/2162402X.2017.1336594

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown