CD11c+ CD123Low Dendritic Cell Subset and the Triad TNF-α/IL-17A/IFN-γ Integrate Mucosal and Peripheral Cellular Responses in HIV Patients With High-Grade Anal Intraepithelial Neoplasia: A Systems Biology Approach

Background:The incidence of anal cancer has increased over the past 25 years, and HIV/HPV coinfection is the most important risk factor for anal squamous cell carcinoma. In this study, we demonstrated that the evaluation of systemic and compartmentalized anal mucosa immune response is relevant to differentiating HIV(+) patients at risk of anal intraepithelial neoplasia (AIN).Methods:A systems biology approach was used to integrate different immunological parameters from anal mucosal tissue and peripheral blood assessed by phenotypic and intracytoplasmic analysis of lymphocytes and dendritic cell subsets.Results:Our data demonstrated that anal mucosal mononuclear cells from AIN(+)HIV(+) patients showed a robust capacity in producing proinflammatory/regulatory cytokines, mainly mTNF- > IL-4 > IL-10 > IL-6 = IL-17A. Mucosal TNF-/IFN-/IL-17A are selective high-grade squamous intraepithelial lesion (HSIL)-related biomarkers. Higher levels of circulating CD11c(+)CD123(Low)cells and CD1a(+) cells along with elevated levels of IFN-(+)CD4(+) T cells are major features associated with HSIL in AIN(+)HIV(+) patients. Regardless of the presence of AIN, HIV(+) patients presented a complex biomarker network, rich in negative connections. Among those patients, however, HSIL+ patients displayed stronger positive links between peripheral blood and anal mucosa environments, exemplified by the subnet of IL-17A/TNF-/CD4(+)IFN-(+)/CD11c(+)CD123(Low) cells.Conclusions:The significant association between HSIL and the levels of TNF-/IL-17A/IFN- along with the different subsets of DCs present in the anal mucosa milieu should be studied in more detail as a way to identify and categorize HIV(+) patients vis a vis the high risk of anal cancer outcome.