Human papillomavirus infection

Human papillomavirus infection (HPV infection) is caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and results in either warts or precancerous lesions. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat. Nearly all cervical cancer is due to HPV and two strains – HPV16 and HPV18 – which account for 70% of cases. HPV16 is responsible for almost 90% of HPV-positive oropharyngeal cancers. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.

Vaccination with a nanoparticle E7 vaccine can prevent tumor recurrence following surgery in a human papillomavirus head and neck cancer model

Gabriele Galliverti, Vincent Roh

High-risk human papillomavirus (HPV) encoding E6/E7-HPV oncogenes are responsible for a subgroup of head and neck squamous-cell carcinoma (HNSCC) and thus therapeutic E7-vaccines may be used to control HPV+HNSCC tumors. Herein we investigated the effects of an optimized nanoparticle-conjugated E7 long-peptide vaccine adjuvanted with CpG (NP-E7LP) in an orthotopic immunocompetent mouse model of HPV+HNSCC which is based on injection of HPV16 E6/E7-expressing mEERL95-cells into the submental space. In absence of surgery, vaccination performed before or after tumor-cell injection decreased tumor growth or prolonged mice survival only marginally, despite the high numbers of vaccine-induced circulating E7-specific IFN-gamma-secreting CD8(+) T-cells. This contrasts with the high-efficacy of NP-E7LP-vaccination reported in the genital and subcutaneous HPV16-E6/E7-expressing TC-1 models. Our data show that in a direct comparison, NP-E7LP-vaccination fully controlled TC-1, but not mEERL95, tumors subcutaneously growing in the flanks. Immune-cell infiltration was 10-fold higher in TC-1-tumors, than in mEERL95-tumors, suggesting that vaccine-induced CD8(+) T-cells can only poorly infiltrate mEERL95-tumors. Indeed, immunofluorescence staining of orthotopic mEERL95-tumors showed that CD3(+) T-cells are preferentially located peritumorally. However, when NP-E7LP-vaccination was performed after mEERL95-cell injection, but before resection of primary tumors, no postsurgical recurrence was observed and 100% of the mice survived until the experimental endpoint (day 70) in the NP-E7LP-vaccinated group. In contrast, we observed a 60% recurrence rate and only 35% survival in PBS-vaccinated mice. This suggests that removal of the primary tumor modified the tumor microenvironment, allowing a therapeutic effect of the vaccine-induced anti-tumor response. E7-vaccination combined with surgery may thus benefit patients with HPV+HNSCC.

TAYLOR & FRANCIS INC2021

Hedgehog pathway regulators influence cervical cancer cell proliferation, survival and migration

Peter Martin Beard, Ivana Samarzija

Human papillomavirus (HPV) infection is considered to be a primary hit that causes cervical cancer. However, infection with this agent, although needed, is not sufficient for a cancer to develop. Additional cellular changes are required to complement the action of HPV, but the precise nature of these changes is not clear. Here, we studied the function of the Hedgehog (Hh) signaling pathway in cervical cancer. The Hh pathway can have a role in a number of cancers, including those of liver, lung and digestive tract. We found that components of the Hh pathway are expressed in several cervical cancer cell lines, indicating that there could exist an autocrine Hh signaling loop in these cells. Inhibition of Hh signaling reduces proliferation and survival of the cervical cancer cells and induces their apoptosis as seen by the up-regulation of the pro-apoptotic protein cleaved caspase 3. Our results indicate that Hh signaling is not induced directly by HPV-encoded proteins but rather that Hh-activating mutations are selected in cells initially immortalized by HPV. Sonic Hedgehog (Shh) ligand induces proliferation and promotes migration of the cervical cancer cells studied. Together, these results indicate pro-survival and protective roles of an activated Hh signaling pathway in cervical cancer-derived cells, and suggest that inhibition of this pathway may be a therapeutic option in fighting cervical cancer. (C) 2012 Elsevier Inc. All rights reserved.

Academic Press Inc Elsevier Science2012

Advancing immunotherapy for HPV-related cancers: Improving therapeutic vaccination approaches and understanding the immunosuppressive role of myeloid cells

Gabriele Galliverti

Human Papilloma Viruses (HPVs) are the most common sexually transmitted agents worldwide, and chronic infection with oncogenic HPVs can lead to the development of lesions in the cervix, the vulva, and the head and neck region. In some patients, these lesions will eventually progress to squamous cell carcinomas that have the potential to spread to distant sites. Cervical cancer is by far the most common type of HPV-related malignancy, and at the early stages can be treated quite effectively. However, for patients in the later stages of tumor progression traditional therapeutic approaches like chemotherapy are poorly effective, and the development of novel strategies based on immunotherapy is undergoing. Clinical trials using HPV E6/E7-derived synthetic long peptides (SLPs) vaccines have shown promising results. However, these vaccines are only leading to significant responses in a low percentage of patients bearing pre-malignant lesions, whereas they seem to be completely ineffective in patients with advanced tumors, suggesting the presence of immune-escape mechanisms. Here I describe an improved therapeutic vaccination approach based on conjugation of E7-derived SLPs to solid-phase ultra-small (30 nm in diameter) nanoparticles (NPs). The NP-conjugated formulation (NP-E7LP) was able to significantly enhance both the systemic and local anti-tumor immune responses, leading to higher CD8 T cell infiltrates in the tumor microenvironment (TME) resulting in a significant reduction in tumor burden and overall increased survival in mice bearing transplantable HPV+ TC1 and SC1 tumors. Next, I demonstrate that a transgenic mouse model for HPV-related cancers expressing the HPV16 early region under the keratin 14 promoter bears striking similarities to cervical cancer patients regarding the alteration of the immune system provoked by HPVs. By taking advantage of the K14HPV16 H2b model, I show that the use of a nanoparticle-conjugated vaccine is required to elicit an immune response, but that, similarly to cervical cancer patients, therapeutic vaccination alone is not sufficient to elicit efficacious anti-tumor immunity. I also illustrate that combinatorial trials involving several different therapeutic antibodies are not sufficient to significantly boost the anti-tumor immune response. Finally, I identify a substantial increase in immunosuppressive myeloid cells (MDSCs) as the mechanism likely responsible for the observed impairment of the immune response, a feature that seems to be shared by cervical cancer patients. Interestingly, 5 although the attention of most of the researchers in the field is usually focused on the TME, I provide evidence that this myeloid cell-dependent mechanism is acting upstream in the lymphoid organs where it inhibits the very first steps in the generation of the anti-tumor immune response. My data suggest that this mechanism could potentially put an early stop to the cancer-immunity cycle, thereby contributing to the ineffectiveness of immunotherapies in cervical cancer patients. In summary, this thesis provides new knowledge that will contribute to the improvement of immunotherapy-based approaches against cervical cancer and other HPV-related diseases with the potential for applicability to other types of cancer.

EPFL2018