Abstract
Despite the close association between Kaposi’s sarcoma (KS) and immune dysfunction, it remains unclear whether tumor infiltrating immune cells (TIIC), by their absence, presence, or dysfunction, are mechanistically correlated with KS pathogenesis. Therefore, their potential capacity to serve as prognostic biomarkers of KS disease progression or control is unclear. Because epidemic-KS (EpKS) occurs with HIV-1 co-infection, it is particularly important to compare TIIC between EpKS and HIV-negative African endemic-KS (EnKS) to dissect the roles of HIV-1 and Kaposi Sarcoma-associated herpesvirus (KSHV) in KS pathogenesis. This cross-sectional study of 13 advanced KS (4 EnKS, 9 EpKS) patients and 3 healthy controls utilized single-color immunohistochemistry and dual-color immunofluorescence assays to characterize and quantify KSHV infected cells in relation to various TIIC in KS biopsies. Analysis of variance (ANOVA) and Mann-Whitney tests were used to assess differences between groups where P-values < 0.05 were considered significant. The abundance of KSHV infected cells was heterogeneous in KS biopsies. Despite the presence of T-cell chemoattractant chemokine CxCL-9 in biopsies, CD8+ T-cells were sparsely distributed in regions with evident KSHV infected cells but were readily detectable in regions devoid of KSHV infected cells (P < 0.0001). CD68+ (M1) macrophages were evenly and diffusely distributed in KS biopsies, whereas, the majority of CD163+ (M2) macrophages were localized in regions devoid of KSHV infected cells (P < 0.0001). Overall, the poor immune cell infiltration or co-localization in KS biopsies independent of HIV-1 co-infection suggests a fundamental tumor immune evasion mechanism that warrants further investigation.
Highlights
Increased incidence of Kaposi’s sarcoma (KS) in the Human Immunodeficiency virus type 1 (HIV-1) infected (EpKS), transplant recipients, and in the elderly, implies that immune dysregulation or immune suppression plays a role in tumorigenesis [1, 2]
EpKS patients were all Antiretroviral therapy (ART) experienced with undetectable plasma HIV-1 load, excepting patient C038 and 21242 who were on ART for less than a month and patient C3097 who was experiencing ART failure
Using Dual-Color Immunofluorescence (DIF) co-staining for latency associated nuclear antigen (LANA) and Chemokine ligand 9 (CxCL-9), we found that CxCL-9 was expressed at higher levels in both EpKS and EnKS tissue compared to normal skin, consistent with our published transcriptomics analysis [17] (Figure 2)
Summary
Increased incidence of Kaposi’s sarcoma (KS) in the HIV-1 infected (EpKS), transplant recipients, and in the elderly, implies that immune dysregulation or immune suppression plays a role in tumorigenesis [1, 2]. Despite the close association between KS and immune dysfunction [5], it remains unclear whether TIIC are a critical component in KS pathogenesis, and whether their absence, presence, or dysregulation could serve as a prognostic biomarker of KS disease progression or control. This is relevant for comparison of EpKS to EnKS where the disease presentation, pathology and humoral immune parameters appear to be highly similar and the direct or indirect role of HIV-1 in KS remains unclear [5]
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