Cervical cancer (CC) is the 4th most common cause of death from tumor in women worldwide, and virtually all CC are caused by sexually-transmitted high-risk human papilloma viruses (hrHPVs). In general, it takes 10 to 20 years for the premalignant condition to progress to cancer, reflecting the inability of host immunity to clear abnormal cells. Indeed, hrHPVs are notorious for their ability to evade immune responses and to avoid direct recognition of infected/transformed cells by cytotoxic lymphocytes. In addition, hrHPVs suppress type I IFN pathways, thus adding a further level of immunosuppression.
Among the cytosolic proteins regulating IFN-I production is ADAR1, an RNA editing enzyme that converts adenosines to inosines within double-stranded RNA, leading to diversification of both transcriptome and proteome landscapes. In most tumors, hyper-editing of RNA by elevated ADAR1 activity results in suppression of immunity, while ADAR1 ablation enhances activation of cytoplasmic innate immune sensors and IFN-signaling, resulting in reduced cancer cell viability.
Hence, our hypothesis is that ADAR1 plays a critical role in hrHPV-driven CC, through its ability to suppress IFN-I and immune responses mediated by innate lymphocytes. To address these issues, we will: 1) characterize ADAR1 expression in cervical biopsies from different groups of CC patients, and correlate it with disease stage and/or patient survival; 2) dissect the impact that ADAR1 manipulation has on IFN-I signaling pathways, pro-inflammatory cytokine production and innate lymphocyte-mediated immune responses (NK and ILCs).
We aim to identify novel mechanisms of immune suppression sustaining HPV-driven tumorigenesis and to characterize NK/ILC subsets endowed with distinct functional properties that can affect CC progression. We expect that our findings will pose the basis for future studies aiming at reactivating innate immunity via the delivery of small RNAs antagonizing ADAR1 and with anti-tumor effect.
We believe our project has several implications and impacts at scientific and technological levels, in Public Health and socio-economic aspects, as well as in teaching/training of PhD students and post-docs.
- Scientific knowledge and development of technologies.
The results of this project might ultimately lead to improve the comprehension of the biology of HPV-related cancer progression and of the impaired NK cell/ILC innate immune responses against transformed keratinocytes. The role of NK cells in the natural history of HPV infection and HPV-driven tumorigenesis is not well understood, while the role of ILCs has not been reported yet. Moreover, the interplay between ADAR1, IFN-I and NK cells/ILCs has never been addressed before in CC as well as in any other type of cancer. Therefore, our major expectation is to identify novel mechanisms and regulators suppressing the innate immune responses in hrHPV-transformed cells, with the ultimate goal of opening the possibility to new therapeutic targets and interventions. In fact, the data collected in this study will create the basis to further develop the project. Indeed, our aim is to develop a breakthrough technological therapeutic approach antagonizing ADAR1, such as nanoparticle delivery of ADAR1-specific siRNA.
- Applications for Public Health and socio-economic impacts.
Cervical carcinoma is among the top 5 cancers affecting women globally. The incidence rate of the disease is even more high in developing countries due to lack of awareness, followed by mass screening programs, various socioeconomic issues, and low usage of preventive vaccines. However, increasing investments and interests from the Pharma and Industrial sectors are on the development of implemented HPV-vaccines The different tasks pursued will permit a better understanding of the mechanisms underlying HPV-driven tumorigenesis and will improve the Healthcare and Health System (by reducing the costs of therapies through better effectiveness and by optimizing the social environment). The results will eventually allow to verify the effects of innate immune cell reactivation through nanoparticle delivery of small RNAs targeting ADAR1. This approach could represent a new, low-cost and relatively easy-to-make therapeutic modality for the treatment of HPV-related cancers. Our approach bodes well especially in light of the recent success of the COVID-19 vaccines which are long stretches of chemically modified mRNA sequences.
- Impact in teaching and training.
One main goal of the project is also to target young scientists. Training activities of PhD students and post-docs will insure the acquisition of new techniques and scientific knowledge.