Human papillomaviruses (HPV) are the causative agent of squamous cervical carcinoma. The HPV-associated transformation is a multistep process that can occur after several years from the infection. During this time HPV can alter proliferation and other numerous mechanisms of the infected cell, mainly through the action of E6 and E7 proteins. Exploitation of the tumor microenvironment (TME) to impair immune response is an important feature of HPV-associated tumorigenesis even if the complexity and the plasticity of the TME offer compelling reasons to hypothesize some other roles. Damage associated molecular patterns (DAMPs) are a large family of autologous molecules that convey "danger signals" from both stressed and death cells. A specific inflammatory response arises when the right signal is sensed from the right receptor. High mobility group box 1 (HMGB1) is a non-histone nuclear protein that is passively released extracellularly by necrotic cells or actively secreted by activated immune cells. Once in the extracellular environment, it can bind different receptors thereby activating pro- or anti-inflammatory responses, depending by the context. Since HPV-related carcinogenesis is an invasive and stressful process that lasts some years, it is reasonable to suppose that DAMPs can participate at the HR-HPV persistent infection. Based on previous data showing that HR-HPV transformed keratinocytes can build an immunosuppressive TME, the purpose of this project is to evaluate the possible involvement, with anti-inflammatory role, of HMGB1 in a high-risk (HR)-HPV-positive cellular model. The objective of the project is to define new-insight into the DAMPs role in the HPV-related tumorigenesis.
The project combines cellular and molecular biology, biotechnology and immunology knowledge with a view to expand current understanding on pathogenic mechanism of HPV infections and related tumors. The working group of the proposing researcher has already been involved in research projects on HPVs. On the basis of his background and expertise on this relevant issue of human health, the goal of the project is to study the role of HMGB1 in the TME of HPV-induced carcinoma. The present project mainly focuses on the study of the involvement of inflammatory microenvironment in the HPV-induced carcinogenesis, approaching the analysis of the role of the DAMPs as well as their delivery and the functions in the carcinogenesis process. A new insight evaluated in this project is the possibility that HMGB1 could damp immune response favoriting the escape from immune system by HPV-positive cells. Accomplishing this task will have also relevant impact on the ongoing development of experimental strategies based on extracellular vesicles delivery and/or stimulation, since it would represent a possible way to evaluate the plasticity of immunosuppressive/proinflammatory TME in the HPV-induced carcinogenesis.