Lack of CD8+ T-cell co-localization with Kaposi’s sarcoma-associated herpesvirus infected cells in Kaposi’s sarcoma tumors

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.

Assessing immune infiltration and the tumor microenvironment for the diagnosis and prognosis of sarcoma

“…Previous report showed that TGF-β suppresses CD8+ effector T-cell function, inhibits the Th1 phenotype, and activates M2 macrophages polarization, driving immune cells from the tumor compartment [ 45 ]. We found that the CD8 T cell fraction was negatively associated with M0 and M2 macrophages, and positively associated with M1 macrophages in sarcomas samples, consistent with the previous reports [ 46 , 47 ], suggesting that CD8 T cells and macrophages may be potential markers for the prognosis of patients with sarcoma.…”

Assessing immune infiltration and the tumor microenvironment for the diagnosis and prognosis of sarcoma

“…Previous report showed that TGF-β suppresses CD8+ effector Tcell function, inhibits the Th1 phenotype, and activates M2 macrophages polarization, driving immune cells from the tumor compartment [45]. We found that the CD8 T cell fraction was negatively associated with M0 and M2 macrophages, and positively associated with M1 macrophages in sarcomas samples, consistent with the previous reports [46,47], suggesting that CD8 T cells and macrophages may be potential markers for the prognosis of patients with sarcoma.…”

Cells of the Innate and Adaptive Immune Systems in Kaposi’s Sarcoma

“…In HIV-associated KS patients, neutrophil function has been reported to be compromised [ 27 ]. This is supported by a recent study on tumor infiltrating immune cells in KS tumors, which did not observe any neutrophil infiltration in KS tumor biopsies [ 28 ]. Therefore, the KS tumor environment and associated cytokines which are elevated in KS patients, such as IL-6, may also contribute towards KS immune evasion through the neutrophil pathway.…”

“…In one study, it was observed that KSHV-specific CTLs were not recruited to KS lesions in KSHV-infected individuals who progressed to KS [ 78 ]. This is supported by a more recent study that observed and reported statistically significant sparse distribution of CD8 + T cells in regions of KS tumor biopsies with evident KSHV-infected cells compared to regions of KS tumor biopsies that were devoid of KSHV infection which had readily detectable CD8 + T cells [ 28 ].…”

“…This is also supported by a study that identified monocytes as a reservoir for KSHV in KS tumors [ 36 ]. Furthermore, macrophages have also been observed to be evenly distributed and in high numbers in KS tumors [ 28 ] and may provide a reservoir of KSHV.…”