Abstract
Langerhans cells (LCs) are the antigen-presenting cells of the epithelial layer and are responsible for initiating immune responses against skin and mucosa-invading viruses. Human papillomavirus (HPV)-mediated suppression of LC function is a crucial mechanism of HPV immune evasion, which can lead to persistent infection and development of several human cancers, including cervical, anal, and head and neck cancers. The cell-derived cytokine-based biologic, IRX-2, consists of multiple well-defined cytokines and is broadly active on various immune cell subsets. In this study, we investigated primary human LC activation after exposure to HPV16, followed by treatment with IRX-2 in vitro, and evaluated their subsequent ability to induce HPV16-specific T cells. In contrast to its activity on dendritic cells, HPV16 alone is not sufficient to induce phenotypic and functional activation of LCs. However, IRX-2 induces a significant upregulation of antigen presentation and costimulatory molecules, T helper 1 (Th1)-associated cytokine release, and chemokine-directed migration of LCs pre-exposed to HPV16. Furthermore, LCs treated with IRX-2 after HPV16 exposure induced CD8+ T-cell responses against specific HLA-A*0201-binding HPV16 T-cell epitopes. The present study suggests that IRX-2 is an attractive immunomodulator for assisting the immune response in eradication of HPV-infected cells, thereby potentially preventing HPV-induced cancers.
Highlights
Persistent high-risk human papillomavirus infection leads to the development of numerous human cancers, including cervical, vaginal, vulvar, anal, and an increasing proportion of head and neck cancers, which cause significant morbidity and mortality worldwide (Tota and others 2011; Forman and others 2012)
The phenotype of immature Langerhans cells (LCs) derived from monocytes was defined as high expression of major histocompatibility complex (MHC) class I, class II, and CD1a with low expression of costimulatory molecules and maturation markers, CD40, CD80, CD83, CD86, and CCR7 (Fig. 1, solid gray histograms), similar to what has been shown for LCs isolated from skin ex vivo (Flacher and others 2006)
Immature LCs were incubated with a 1:2 dilution of IRX-2 with resultant concentrations of 3.2 ng/mL IL-2; 0.4 ng/mL IL1b; 1.2 ng/mL interferon gamma (IFNg); 2.0 ng/mL tumor necrosis factor alpha (TNFa); and 0.7 ng/mL IL-6, and the same dilution was used throughout this study
Summary
Persistent high-risk human papillomavirus (hrHPV) infection leads to the development of numerous human cancers, including cervical, vaginal, vulvar, anal, and an increasing proportion of head and neck cancers, which cause significant morbidity and mortality worldwide (Tota and others 2011; Forman and others 2012). The percentage of girls in the United States completing the recommended vaccine schedule was only 37.6% in 2013 (Stokley and others 2014). These vaccines provide no protection against disease for the hundreds of millions of people who are already infected with HPV. A significant number of individuals are still at risk for developing HPV-related cancer as they are already infected, have not been vaccinated, or will become infected by an HPV type not covered in the current bivalent and quadrivalent vaccines, emphasizing the need to expand HPVrelated cancer prophylaxis strategies
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