A Systematic Review of Expression and Immunogenicity of Human Endogenous Retroviral Proteins in Cancer and Discussion of Therapeutic Approaches.

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced in healthy somatic cells, there are numerous reports of HERV transcription and translation across a wide spectrum of cancers, while T and B cell responses against HERV proteins have been detected in cancer patients. This review systematically categorizes the published evidence on the expression of and adaptive immune response against specific HERVs in distinct cancer types. A systematic literature search was performed using Medical Search Headings (MeSH) in the PubMed/Medline database. Papers were included if they described the translational activity of HERVs. We present multiple tables that pair the protein expression of specific HERVs and cancer types with information on the quality of the evidence. We find that HERV-K is the most investigated HERV. HERV-W (syncytin-1) is the second-most investigated, while other HERVs have received less attention. From a therapeutic perspective, HERV-K and HERV-E are the only HERVs with experimental demonstration of effective targeted therapies, but unspecific approaches using antiviral and demethylating agents in combination with chemo- and immunotherapies have also been investigated.

Efficacy and Synergy with Cisplatin of an Adenovirus Vectored Therapeutic E1E2E6E7 Vaccine against HPV Genome-Positive C3 Cancers in Mice.

Human papillomavirus (HPV) infections are the main cause of cervical and oropharyngeal cancers. As prophylactic vaccines have no curative effect, an efficient therapy would be highly desired. Most therapeutic vaccine candidates target only a small subset of HPV regulatory proteins, namely, E6 and E7, and are therefore restricted in the breadth of their immune response. However, research has suggested E1 and E2 as promising targets to fight HPV+ cancer. Here, we report the design of adenoviral vectors efficiently expressing HPV16 E1 and E2 in addition to transformation-deficient E6 and E7. Vaccination elicited vigorous CD4+ and CD8+ T-cell responses against all encoded HPV16 proteins in outbred mice and against E1 and E7 in C57BL/6 mice. Therapeutic vaccination of C3 tumor-bearing mice led to significantly reduced tumor growth and enhanced survival for both small and established tumors. Tumor biopsies revealed increased numbers of tumor-infiltrating CD8+ T cells in treated mice. Cisplatin enhanced the effect of therapeutic vaccination, accompanied by enhanced infiltration of dendritic cells into the tumor. CD8+ T cells were identified as effector cells in T-cell depletion assays, seemingly under regulation by FoxP3+CD4+ regulatory T cells. Finally, therapeutic vaccination with Ad-Ii-E1E2E6E7 exhibited significantly enhanced survival compared with vaccination with two peptides each harboring a known E6/E7 epitope. We hypothesize that this difference could be due to the induction of additional T-cell responses against E1. These results support the use of this novel vaccine candidate targeting an extended set of antigens (Ad-Ii-E1E2E6E7), in combination with cisplatin, as an advanced strategy to combat HPV+ cancers.

Preferential Expansion of HPV16 E1-Specific T Cells from Healthy Donors' PBMCs after Ex Vivo Immunization with an E1E2E6E7 Fusion Antigen.

Persistent human papillomavirus (HPV) infection is responsible for practically all cervical and a high proportion of anogenital and oropharyngeal cancers. Therapeutic HPV vaccines in clinical development show great promise in improving outcomes for patients who mount an anti-HPV T-cell response; however, far from all patients elicit a sufficient immunological response. This demonstrates a translational gap between animal models and human patients. Here, we investigated the potential of a new assay consisting of co-culturing vaccine-transduced dendritic cells (DCs) with syngeneic, healthy, human peripheral blood mononuclear cells (PBMCs) to mimic a human in vivo immunization. This new promising human ex vivo PBMC assay was evaluated using an innovative therapeutic adenovirus (Adv)-based HPV vaccine encoding the E1, E2, E6, and E7 HPV16 genes. This new method allowed us to show that vaccine-transduced DCs yielded functional effector T cells and unveiled information on immunohierarchy, showing E1-specific T-cell immunodominance over time. We suggest that this assay can be a valuable translational tool to complement the known animal models, not only for HPV therapeutic vaccines, and supports the use of E1 as an immunotherapeutic target. Nevertheless, the findings reported here need to be validated in a larger number of donors and preferably in patient samples.