HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Abstract

HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.

HNSCC: Tumour Antigens and Their Targeting by Immunotherapy

“…E2 has already been successfully targeted using an MVA E2 recombinant vaccinia virus in anogenital intraepithelial lesions with complete elimination in 89.3% of female (total of n = 1176) and 100% of male (total of n = 180) patients [ 73 ]. A number of additional vaccines targeting E5 are in preclinical development [ 74 , 75 , 76 , 77 ]. However, no clinical data on targeting E2 and E5 in head and neck cancer are available.…”

Development of HPV16,18,31,45 E5 and E7 peptides-based vaccines predicted by immunoinformatics tools

“…The recent studies have indicated the important role of E5 oncoprotein in cell transformation, tumourigenesis, and immune modulation (Venuti et al 2011). The researchers showed that HPV16 E5 oncoprotein was expressed in early stage of carcinogenesis and could be a target of immunotherapy (Paolini et al 2017). On the other hand, the presence of E5 viral transcripts could be a major marker of active viral infection, and subsequently a target of immunotherapy.…”

A multi-genotype therapeutic human papillomavirus vaccine elicits potent T cell responses to conserved regions of early proteins

“…Paolini et al . reported the detection of E5 transcripts in nearly 70 clinical samples, including lesions with HPV-related changes and low or high-grade abnormalities, indicating a possible biological activity of E5 products 26 . Given the contribution of E5 to malignant progression it may also be an important target.…”

“…E2 initiates and maintains viral replication and T cell responses to E2 are associated with regression of CIN and viral clearance 19,20,24,25 . E5 cooperates with E6 and E7 oncogenes to promote hyper-proliferation of infected cells and is therefore crucial for malignant progression 26,27 . HPV16 and HPV18 cause at least 70% of cervical cancers and thus have been the focus of most interventions to date 28,29 .…”